Time and Temperature Dependent Palladium-Catalyzed Stereo- A nd Regioselective Alkoxy-arylation of Triple Bonds: Synthesis of (E)/(Z)-1,1-Disubstituted-3-(1-Phenylalkylidene)-1,3-dihydroisobenzofurans

Article abstract of DOI:10.1021/acs.joc.1c00666

The development of synthetic strategies enabling the stereo- A nd regio-selective synthesis of organic molecules is indispensable in the pharmaceutical industry. This work describes a stereo- A nd regioselective synthesis of (E)/(Z)-1,1-disubstituted-3-(1-arylalkylidene)-1,3-dihydroisobenzofurans catalyzed by palladium. The DHIBFs are achieved from readily available aryl bromides and ortho-alkyne tertiary alcohols via intermolecular aryl Heck coupling and intramolecular oxo-cyclization of the suitably situated hydroxyl group. Significantly, it was demonstrated that a Z-isomer was formed as a substantial isomer at 80 °C for 6 h, whereas the stable E-isomer was the predominant one at slightly vigorous conditions (100 °C for 12 h). In addition, careful observation has also led to the realization that this double isomerization from Z-to E-isomer was triggered in the NMR tube itself in CDCl3 at room temperature. Significantly, this protocol, for the first time, enabled the synthesis of heavily substituted dihydroisobenzofurans, especially, bearing a tetra-substituted double bond.

Full text of DOI:10.1021/acs.joc.1c00666

pubs.acs.org/joc
Article
Time and Temperature Dependent Palladium-Catalyzed Stereo- and
Regioselective Alkoxy-arylation of Triple Bonds: Synthesis of (E)/
(Z)‑1,1-Disubstituted-3-(1-Phenylalkylidene)-1,3-
dihydroisobenzofurans
Chinnabattigalla Sreenivasulu and Gedu Satyanarayana*
Cite This: J. Org. Chem. 2021, 86, 8182−8196
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: The development of synthetic strategies enabling the stereo- and regio-selective synthesis of organic molecules is
indispensable in the pharmaceutical industry. This work describes a stereo- and regioselective synthesis of (E)/(Z)-1,1-disubstituted-
3-(1-arylalkylidene)-1,3-dihydroisobenzofurans catalyzed by palladium. The DHIBFs are achieved from readily available aryl
bromides and ortho-alkyne tertiary alcohols via intermolecular aryl Heck coupling and intramolecular oxo-cyclization of the suitably
situated hydroxyl group. Significantly, it was demonstrated that a Z-isomer was formed as a substantial isomer at 80 °C for 6 h,
whereas the stable E-isomer was the predominant one at slightly vigorous conditions (100 °C for 12 h). In addition, careful
observation has also led to the realization that this double isomerization from Z- to E-isomer was triggered in the NMR tube itself in
CDCl3 at room temperature. Significantly, this protocol, for the first time, enabled the synthesis of heavily substituted
dihydroisobenzofurans, especially, bearing a tetra-substituted double bond.
time, the intramolecular cyclization of 2-(1-alkynyl) tertiary
benzylic alcohols was also well explored (Figure 1). Larock et
al. demonstrated the synthesis of 1H-isochromenes and 1,3-
dihydroisobenzofurans by iodocyclizations of 2-alkyne benzylic
alcohols (Figure 1a).25 Simultaneously, the research group of
Costa presented the sequential nucleophilic ring-opening and
heterocyclization, followed by oxidative carbonylation of
alkynyloxiranes (Figure 1b).26 Zhu and co-workers described
the synthesis of 1,3-dihydroisobenzofurans using copper
catalysis (Figure 1c).11 In 2012, Perumal et al. reported the
synthesis of 1,3-dihydroisobenzofurans and their antidepres-
sant activity (Figure 1d).11 In 2016, You et al. revealed the
synthesis of dihydroisobenzofurans via alkyne/alkene directed
INTRODUCTION
■
The dihydroisobenzofurans are major building blocks in the
natural product synthesis and are used as a core nucleus in
many bioactive compounds.1 Particularly, 1,3-dihydroisoben-
zofuran (phthalan) derivatives are known to exhibit a wide
variety of drug-like properties,2−5 such as potent antioxidant,6
antidepressant, antihistaminic,7 anti-inflammatories,8,9 and
antifungal properties, etc.10,11 Therefore, the synthesis of
dihydroisobenzofurans has drawn considerable attention from
the synthetic community. Generally, the intramolecular
cyclizations of 2-alkynyl phenyl ketones have been well
explored to accomplish isobenzofurans,12 isocoumarins,13
isoindoline-1-ones,14 cyclic imidates,15 and dihydroisobenzo-
furans.16−19 Jiang et al. reported the β-alkynyl ketones
chemistry to synthesize spiro- and dispiro-1H-chromenes/
chromenes.20−23 Later on, the same group explored the
synthesis of isobenzofurans from β-alkynyl ketones via Pd(II)
catalysis,12 concomitantly reporting the synthesis of sulfonated
1,3-dihydroisobenzofurans from β-alkynyl ketones via a radical
MCR (Multi-Component Reactions) process.24 At the same
Received: March 20, 2021
Published: June 7, 2021
https://doi.org/10.1021/acs.joc.1c00666
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 8182−8196
8182

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Figure 1. A comparison chart of earlier versus the present study to dihydroisobenzofurans.
5-exo-dig cyclization (Figure 1e).27 Intramolecular hydro-
alkoxylation of 2-(1-alkynyl) tertiary benzylic alcohols was
reported by Yu et al. (Figure 1f).28 A palladium-catalyzed
tandem oxocyclization/coupling process of ethyl 3-(2-
alkynylphenyl)-3-oxopropanoates with aryl iodides to furnish
dihydroisobenzofurans has been developed by Wu in 2015
(Figure 1g).16 The research group of Gabriele has reported the
synthesis of (Z)-1-alkylidene-1,3-dihydroisobenzofurans and
1H-isochromenes via cycloisomerization of 2-alkynylbenzyl
alcohols by a palladium catalyst (Figure 1h).18 In our earlier
work, we described the dihydroisobenzofurans synthesis via
Sonogashira coupling and subsequent intramolecular 5-exo-dig
cyclization (Figure 1i).29 To date, a reasonable number of
reports were accomplished on the synthesis of dihydroiso-
benzofurans, majorly with a tri-substituted double bond
moiety. In this respect, the synthesis of dihydroisobenzofurans
with a tetra-substituted double bond has been scarcely
explored.17,30−33 Nevertheless, to the best of our knowledge,
no report was developed on the synthesis of tetra-substituted
exocyclic double bond containing 1,1-dialkyl/1,1-alkyl/1,1-
diaryl-3-(1-arylalkylidene)-1,3-dihydroisobenzofurans. Herein,
we present stereo- and regioselective synthesis of E- and Z-
isomers of dihydroisobenzofurans from 2-(1-alkynyl) tertiary
benzylic alcohols and aryl bromides via an intermolecular aryl
Heck coupling and intramolecular oxo-cyclization path.
Notably, it was observed that the process is time and
temperature dependent to form the Z- or E-isomer of the
product.
RESULTS AND DISCUSSION
■
The initial investigation began by choosing 2-(2-(oct-1-yn-1-
yl)phenyl)propan-2-ol 1a and bromobenzene 2a as the model
substrates. At first, the reaction was performed in the presence
of Pd(OAc)2, ligand PPh3, and base Cs2CO3 at 110 °C in
toluene (1.5 mL) for 24 h. The expected product
dihydroisobenzofuran 3aa was obtained in moderate (48%)
yield (Table 1, entry 1). At the same time, the reaction with
Na2CO3 and Ag2CO3 as mild bases furnished the product 3aa,
in 34% and 33% yields, respectively (Table 1, entries 2 and 3).
When the reaction was conducted in the presence of base
CsCO3 and Ag2O as an additive (1 equiv), the yield of 3aa was
further dropped to 20% yield (Table 1, entry 4). Also, the
combination of Na2CO3 (2 equiv) and Ag2O (0.2 mmol) was
inferior and led to a complex mixture (Table 1, entry 5). When
X-Phos was used as a ligand in place of PPh3, trace amounts of
3aa were observed (Table 1, entry 6). On the other hand, the
reaction with reduced reaction times of 12 and 6 h afforded
3aa with slightly increased yields of 51% and 55%, respectively
(Table 1, entries 7 and 8). Further decreasing the reaction time
to 2 h at 110 °C gave 3aa in 61% yield (Table 1, entry 9).
8183
https://doi.org/10.1021/acs.joc.1c00666
J. Org. Chem. 2021, 86, 8182−8196

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a b c d e f
, , , , ,
Table 1. Optimization of Reaction Conditions
S no.
ligand
base (2 equiv)
temp (°C)
time (h)
yield (%) 3aa and 4aa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
PPh3
PPh3
PPh3
PPh3
PPh3
X-Phos
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
Cs2CO3
Na2CO3
Ag2CO3
Cs2CO3
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
110
110
110
110
110
110
110
110
110
110
100
100
80
80
80
80
80
100
100
100
24
24
24
24
24
24
12
6
2
2
2
12
2
48 and −
34 and −
33 and −
20 and −
TLC not clear
c
c
trace
51 and −
55 and −
61 and −
d
62 and −
59 and −
82 and −
− and 45
<5 and 80
15 and 72
20 and 57
53 and 12
32 and −
6
12
24
48
12
12
12
e
PPh3
PPh3
− and −
f
54 and −
a
Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), Pd(OAc)2 (0.01 mmol), PPh3 (0.03 mmol), Cs2CO3 (0.4 mmol), toluene (1.5 mL) at 80
b
c
d
e
°C. Isolated yields of the products by column chromatography. Additive Ag2O (0.2 mmol) used. 3 equiv of Cs2CO3 used. The reaction has
been carried out without Pd(OAc)2. Iodobenzene used as arylating agent (0.24 mmol).
f
Increasing the quantity of base Cs2CO3 to 3 equiv furnished
3aa in 62% yield (Table 1, entry 10). In comparison, the
reaction at 100 °C for 2 h led to 3aa in 59% (Table 1, entry
11). Significantly, a prolonged reaction time (12 h) at 100 °C
enhanced the yield to 82% of 3aa (Table 1, entry 12). The
further decrease of temperature to 80 °C for 2 h unpredictably
resulted in a 45% yield of Z-isomeric product 4aa (Table 1,
entry 13). When the reaction was conducted at 80 °C for 6 h,
surprisingly, the product 3aa yield decreased to <5%, and the
Z-isomeric product 4aa yield was increased to 80% (Table 1,
entry 14). Furthermore, increasing the reaction time to 12, 24,
and 48 h at 80 °C resulted in “15% of 3aa and 72% of 4aa”,
“20% of 3aa and 57% of 4aa”, and “53% of 3aa and 12% of
4aa”, respectively (Table 1, entries 15, 16, and 17). The
reaction without PPh3 and with Pd(OAc)2, at 100 °C for 12 h,
delivered 3aa in 32% (Table 1, entry 18). However, when the
reaction was conducted without Pd(OAc)2 and with PPh3 at
100 °C for 12 h, it showed no progress at all (Table 1, entry
19). The reaction was also successful and furnished the
product 3aa in 54% yield when iodobenzene was used instead
of bromobezene 2a (Table 1, entry 20). Overall, this
observation favors the geometrical interconversion from the
thermodynamically less stable Z-isomer to the more stable E-
isomer at the tetra-substituted double bond.
toluene (1.5 mL) for 12 h at 100 °C, for the synthesis of
thermodynamically stable (E)-3-(1-phenylalkylidene)-1,3-dihy-
droisobenzofuran 3aa (Table 1, entry 12), and 1 (0.2 mmol), 2
(0.24 mmol), Pd(OAc)2 (0.01 mmol), PPh3 (0.03 mmol),
Cs2CO3 (0.4 mmol), and toluene (1.5 mL) for 6 h at 80 °C,
for the synthesis of (Z)-3-(1-phenylalkylidene)-1,3-dihydroi-
sobenzofuran 4aa (Table 1, entry 14). Next, we turned to
evaluate the scope and generality of these conventions. This
protocol has wide functional group tolerance; both electron-
deficient (NO2, COMe, CN) and electron-rich aryl bromides
(Me, OMe) are compatible, resulting in a variety of substituted
dihydroisobenzofuran derivatives.
Various 2-(1-alkynyl) tertiary benzylic alcohols 1a−l are
subjected to both electron-rich (3-Me = 2b, 4-Me = 2c, 4-
OMe = 2e, and α-naphthyl = 2d) and electron-deficient (4-
bromoacetophenone = 2i and 4-bromobenzaldehyde = 2l) aryl
bromides under the optimal conditions (Table 1, entry 12),
which resulted in 1,3-dihydroisobenzofurans derivatives 3aa−
gh (Table 2). Apart from the spectrometric evidence, for the
structure determination of dihydroisobenzofuran products 3,
the skeletal structure including the stereo/regioselectivity
around the double bond of 3gh was confirmed from the
single-crystal X-ray diffraction analysis (Figure 2, CCDC:
2071793). The ellipsoids are drawn at a 50% probability level
(see in the Supporting Information for details).
From the optimization study, the standard reaction
conditions are 1 (0.2 mmol), 2 (0.24 mmol), Pd(OAc)2
(0.01 mmol), PPh3 (0.03 mmol), Cs2CO3 (0.4 mmol), and
Surprisingly, when independent coupling reactions were
conducted between 2-(5-methoxy-2-(oct-1-yn-1-yl)phenyl)-
8184
https://doi.org/10.1021/acs.joc.1c00666
J. Org. Chem. 2021, 86, 8182−8196

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a b
,
Table 2. Scope of (E)-1,1-Dialkyl-3-(1-arylalkylidene)-1,3-dihydroisobenzofurans 3aa−ca
a
Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), Pd(OAc)2 (0.01 mmol), PPh3 (0.03 mmol), Cs2CO3 (0.4 mmol), toluene (1.5 mL) at 100
b
°C. Isolated yields of the products by column chromatography.
propan-2-ol 1f with electron-deficient haloarenes 2i and 2l as
arylating agents, they afforded a diastereomeric mixture of
products (3fi:4fi = 4.3:1 ratio, 71%, and 3fl:4fl = 2:1 ratio,
68%). This may be ascribed to the fact that the functional
group’s electron-withdrawing effect derived from haloarene
would make the tetra-substituted double bond of isobenzofur-
8185
https://doi.org/10.1021/acs.joc.1c00666
J. Org. Chem. 2021, 86, 8182−8196

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Figure 2. X-ray structure of the product 3gh with the ellipsoids drawn at the 50% probability level.
an products less nucleophilic and therefore less likely to
undergo geometrical isomerism.
The NMR spectra for converting Z-isomers to the
corresponding stable E-ones are shown in Figure 3. Both (E/
Z, 3/4) isomeric product structures were unambiguously
elucidated by spectroscopic analysis. It is pretty corroborative
to note that the proton NMR analysis of bicyclic
dihydrobenzofuran aromatic proton peaks of E-isomeric
product 3 is more shielded than the Z-isomeric product 4.
This can be explained based on the diamagnetic anisotropy
effect exerted by the other aromatic ring that originated from
aryl bromide in E-isomer 3. The aromatic ring derived from
the haloarene would adopt a perpendicular orientation to the
plane of the bicyclic dihydrobenzofuran ring to relieve the
steric strain. As a result, particularly, the ortho-proton
(highlighted with pink color) would face the diamagnetic
ring current resulting from the other aromatic ring of haloarene
(green one). Hence, the chemical shift of the pink proton
shifted to upfield (i.e., ortho proton of 1 shifted from ∼δ = 7.85
ppm to 5.73 ppm; also, the alkyl groups on the benzylic carbon
and exocyclic double bond connected CH2 proton peaks are
slightly shielded), as shown in Figure 3. Even this sort of
diamagnetic anisotropy is extended to the meta-proton of the
dihydrobenzofuran to a little extent as it is a little farther from
the diamagnetic ring current of the aromatic ring of haloarene.
Further, to estimate the synthetic utility of this strategy, it
was thought to conduct the reaction on a 1.5 mmol scale.
Thus, the reaction of 1c (409 mg, 1.5 mmol) with 2a (283 mg,
1.8 mmol), under the optimal conditions (Table 1, entry 12),
resulted in the desired product 3ca (345 mg, 66%) as shown in
Scheme 1.
As illustrated above (Table 1, entry 14), it would also be
feasible to achieve the stereoselective synthesis of (Z)-3-(1-
phenylalkylidene)-1,3-dihydroisobenzofurans 4, under con-
trolled conditions of the reaction time and the temperature.
Thus, the coupling and cyclo-etherification reactions were
performed on 2-(1-alkynyl) tertiary benzylic alcohols 1a−l
with different substituted haloarenes 2a, 2c, 2d, 2e, and 2h,
under standard conditions. The reaction was found compatible
and afforded the requisite Z-isomeric products (4dd, 4ae, 4ec,
4gd, 4cd, and 4gh) in good yields (Table 3). Delightfully, the
reaction was smooth with bromoarenes connected to electron-
deficient groups, such as 4-bromoacetophenone 2i, 4-nitro-
bromobenzene 2j, 4-nitro-3-fluorobromobenzene 2k, and
methyl 4-bromobenzoate 2m, at 80 °C for 6 h (Table 1,
entry 14). As anticipated, it delivered (Z)-3-(1-phenyl-
alkylidene)-1,3-dihydroisobenzofurans 4 (i.e., 4ai in 79%; 4hj
in 76%, and 4gk in 59% yields, respectively, Table 3). It is
interesting to know that chloro substitution on 2-(1-alkynyl)
tertiary benzylic alcohols 1k also underwent smoothly with
bromobenzene 2a and resulted in 4ka in 73% yield (Table 3).
On the other hand, the reaction with 1,1-diphenyl substitution
on the aromatic ring of 2-(1-alkynyl) tertiary benzylic alcohol
1l with 3-bromotoluene 2b provided the desired product 4lb
in 84% yield (Table 3). Also, the reaction with secondary
benzylic alcohol 1i was successful with an electron-with-
drawing ester moiety on bromoarene 2m, albeit the product
4im was obtained in a moderate 49% yield. The reaction with
primary benzylic alcohol was found to be sluggish and led to
the formation of a complex mixture.
Nevertheless, the above optimization study (Table 1)
noticed that the Z-isomer stereoselectivity seems sensitive to
the reaction’s time and temperature. On the other hand, it may
also be presumed that such a geometrical isomerization would
still be triggered by a nonmetal mediated pathway (i.e., the
time and mild acidic conditions). Therefore, to further
demonstrate this assumption, after confirming the Z-isomer’s
NMR (i.e., for 4ae, 4ec, 4gd, 4cd, 4ka, and 4gh), the
compounds in their respective NMR tubes in CDCl3 solution
were intentionally kept aside for 3 days at room temperature
and resubmitted for NMR spectra (Table 4). To our delight, as
predicted, the NMR spectra analysis revealed the complete
conversion to stable E-isomers of each (i.e., for 3ae, 3ec, 3gd,
3cd, 3ka, and 3gh), as depicted in Table 4. It also noted that
there was no further change from the E-isomer even after a
prolonged time. Whereas with the Z-isomer with more
electron-withdrawing groups such as NO2 and CO2Me derived
from aryl bromide, the rate at which isomerization from Z to E
sluggishly took place [i.e., 4gk:3gk = 83:17 (4-NO2); 4im:3im
= 90:10 (4-CO2Me)], as shown in Table 4.
CONTROL EXPERIMENTS
■
To understand the reaction mechanism of whether the
reaction sequence is proceeding through the initial aryl Heck
coupling across the triple bond, followed by intramolecular
oxo-cyclization, or through an initial intramolecular oxo-
cyclization, followed by intermolecular aryl Heck coupling, it
was some sort to conduct a few control experiments. Thus,
initially, the isobenzofuran 7 was prepared by using the
established copper catalysis process developed by us (Scheme
2a).29 Now, with the compound 7 in hand, next, we explored
the reaction to check the feasibility to undergo intermolecular
Heck reaction across the tri-substituted double bond of 7
under standard conditions of entry 12 of Table 1 (Scheme 2b).
However, the expected Heck product 8 has not been observed
and it led to the isolation of the starting material 7. On the
basis of this observation, the possibility of initial oxo-
cyclization via the formation of an isobenzofuran intermediate
and subsequent Heck coupling path may be precluded. At the
same time, it may be predicted that the reaction proceeds via a
sequence of intermolecular aryl Heck coupling, followed by
intramolecular oxo-cyclization. Further, to rationalize whether
the E-isomeric product is formed directly or initially generating
8186
https://doi.org/10.1021/acs.joc.1c00666
J. Org. Chem. 2021, 86, 8182−8196

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a b
,
Table 3. Synthetic Scope of (Z)-Dihydroisobenzofurans 4dd−im
a
Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), Pd(OAc)2 (0.01 mmol), PPh3 (0.03 mmol), Cs2CO3 (0.4 mmol), toluene (1.5 mL) at 80 °C.
b
Isolated yields of the products by column chromatography.
the Z-isomeric product and then converting into the E-isomer
the conversion of the Z-isomer 4ca to the E-isomer 3ca via
double bond isomerization. As predicted, at the end of the
reaction, the stable E-isomer 3ca was isolated in 69% yield [by
TLC, confirmed the formation of 3ca (Rf (3ca) = 0.8; using
2% ethyl acetate/hexane) at the expense of 4ca], as depicted in
Scheme 2 d, based on which it was understood that the
reaction would prefer the initial Heck reaction on the triple
bond and oxo-cyclization.
in situ in the reaction flask from the Z-isomer, we performed a
reaction between 1c and 2a by using the standard optimal
conditions for the formation of the Z-isomer (Table 1, entry
14; 80 °C, 6 h). After confirming the formation of the Z-
isomer 4ca [by TLC, confirmed that product 4ca (Rf (4ca) =
0.3; using 2% ethyl acetate/hexane) and starting materials 1c
and 2a got consumed], further, the same reaction was
continued at 100 °C for an additional 6 h time, anticipating
8187
https://doi.org/10.1021/acs.joc.1c00666
J. Org. Chem. 2021, 86, 8182−8196

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a b
,
Table 4. Conversion of Z-Isomeric Products 4 to E-Isomeric Products 3
a
b
The percentage of conversion from Z-isomer to E-isomer is as mentioned in the parentheses. The isomeric ratio of Z-/E-isomers is determined
1
from the H NMR spectra.
upon HBr elimination, would yield palladacycle E. The
intermediate D may also be formed directly via a syn-addition
of the aryl and palladium of B across the triple bond in the syn-
direction to the tert-hydroxyl moiety of 1 via path b. Through
reductive elimination of the palladacycle, E forms Z-isomeric
product 4 and regenerates Pd(0) species A. With the
experimental observations, thermodynamically unstable Z-
isomeric product 4 is converting into stable E-isomeric
product 3 in two pathways. One way is in the presence of
PLAUSIBLE REACTION MECHANISM
■
On the basis of the above control experimental observations
(Scheme 2), a plausible mechanism is proposed as depicted in
Scheme 3. Thus, initially, oxidative addition of Pd(0) catalyst
A to aryl bromide generates aryl-Pd(II) species B. Sub-
sequently, syn-addition of the aryl and palladium of B to the
alkyne bond in the anti-direction to the tert-hydroxyl moiety of
1 furnishes C. Then a 180° rotation around the C−C bond of
aryl and alkenyl palladium species gives D via path a, which,
8188
https://doi.org/10.1021/acs.joc.1c00666
J. Org. Chem. 2021, 86, 8182−8196

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1
Figure 3. H NMR spectra of Z-isomeric product 4 converted into E-isomeric product 3.
Scheme 1. Scale-Up Experiment to Give 3ca
palladium catalyst at an elevated temperature like 100 °C and a
prolonged reaction time via intermediate F, as observed in
Scheme 2d. In another way, mild acidic solvent CDCl3 triggers
the isomerization via intermediate G (as noted from Table 4).
In conclusion, this paper dealt with a palladium-catalyzed
intermolecular Heck coupling and intramolecular oxo-cycliza-
tion enabling the access to (E)/(Z-)-(3-(alkyl(aryl)-
methylene)-1,1-dialkyl-1,3-dihydroisobenzofurans, in a highly
stereoselective manner. For the first time, this protocol allows
the synthesis of dihydroisobenzofuran derivatives with a tetra-
substituted double bond. Apart from simple to electron-
donating functional groups, this methodology exhibited a
broad functional group tolerance such as −CHO, −CN,
−COMe, and −NO2 substituents on the haloarene compo-
nent. Moreover, a careful study of the conversion of the
unstable Z-isomer to the relatively more stable E-isomer of 1,3-
dihydroisobenzofurans had revealed interesting insights on the
stereoselective geometrical isomerization of the double bond.
Bruker Avance 400 (400 MHz) spectrometer at 295 K in
CDCl3; chemical shifts (δ ppm) and coupling constants (Hz)
are reported in standard fashion with reference to either
internal standard tetramethylsilane (TMS) (δH = 0.00 ppm) or
CHCl3 (δH = 7.25 ppm). 13C{1H} NMR spectra were recorded
on a Bruker Avance 400 (100 MHz) spectrometer at RT in
CDCl3; chemical shifts (δ ppm) are reported relative to CHCl3
[δC = 77.00 ppm (central line of triplet)]. In the 13C{1H}
NMR, the nature of carbons (C, CH, CH2, and CH3) was
determined by recording the DEPT-135 spectra and is given in
parentheses and noted as s = singlet (for C), d = doublet (for
CH), t = triplet (for CH2), and q = quartet (for CH3). In the
1H NMR, the following abbreviations were used throughout: s
= singlet, d = doublet, t = triplet, q = quartet, qui = quintet,
sept = septet, dd = doublet of doublet, m = multiplet, and brs =
broad singlet. The assignment of signals was confirmed by 1H,
13C{1H} CPD, and DEPT spectra. High-resolution mass
spectra (HR-MS) were recorded on an Agilent 6538 UHD
Q-TOF electron spray ionization (ESI) mode and atmospheric
pressure chemical ionization (APCI) modes. Melting points
are recorded using Tempo and Mettler FP1 melting point
apparatus in capillary tubes and are uncorrected. A single
GENERAL
■
IR spectra were recorded on a Bruker Tensor 37 (FTIR)
spectrophotometer. 1H NMR spectra were recorded on a
8189
https://doi.org/10.1021/acs.joc.1c00666
J. Org. Chem. 2021, 86, 8182−8196

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 2. Control Experiments
Scheme 3. Plausible Reaction Mechanism for the Formation of 3/4
crystal of 3gh was selected and mounted on an Oxford
SuperNova, Dual, Cu at zero, Eos diffractometer. The crystal
was kept at 298 K during data collection. Using Olex2, the
structure was solved with the olex2.solve structure solution
program using direct methods, and refined with the olex2.
refinement package using Gauss−Newton minimization. All
small-scale dry reactions were carried out using Schlenk tubes
under an inert atmosphere. Reactions were monitored by TLC
on silica gel using a combination of hexane and ethyl acetate as
eluents. Reactions were generally run under argon or a
nitrogen atmosphere. Solvents were distilled before use;
mesh) was used for column chromatography (approximately
20 g per 1 g of crude material). Pd(OAc)2, cesium carbonate,
triphenylphosphine (TPP), 4-bromotoluene, 4-bromoanisole,
3-bromotoluene, and 1-nitro-4-bromobenzene were purchased
from Sigma-Aldrich and used as received. Substituted
benzaldehydes, alkyl iodide/bromide, 1-alkynes, and bromo-
benzene, 1-bromonaphthalene, 4-bromoacetophenone, 4-bro-
mobenzaldehyde, 2-bromobenzaldehyde, 4-bromomethyl ben-
zoate, and 4-bromo-2-fluoro-1-nitrobenzene were purchased
from TCI/local.
EXPERIMENTAL SECTION
petroleum ether with a boiling range of 60−80 °C was used.
■
Bromination of aromatics has been carried out in dry
methanol. All Grignard reactions were performed in dry
ether solvent. Palladium-catalyzed reactions were done in dry
toluene. Methanol was distilled under a nitrogen atmosphere
using LiAlH4 and toluene solvent deoxygenated by distillation
over sodium benzophenone under argon and then distilled and
stored in a nitrogen atmosphere. Acme’s silica gel (60−120
General Procedure for the Preparation of E-Isomer (1,3-
Dihydroisobenzofurans 3): GP 1. To a solution of 2-(2-(alkyl-1-
yn-1-yl)phenyl)alkyl/phenyl-2-ol 1a−k (46−59 mg, 0.2 mmol) in dry
toluene (2 mL) were added aryl bromide 2a−l (38−81 mg, 0.24
mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8 mg, 0.03 mmol), and
Cs2CO3 (130 mg, 0.4 mmol) under a nitrogen atmosphere. The
resultant reaction mixture was stirred at 100 °C (oil bath), for 8−12
h. Completion of the reaction was monitored by TLC (5:95 ethyl
8190
https://doi.org/10.1021/acs.joc.1c00666
J. Org. Chem. 2021, 86, 8182−8196

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
acetate and hexane). The reaction mixture was cooled to room
temperature and extracted with ethyl acetate (3 × 15 mL). The
combined organic layers were washed with brine solution, dried
(Na2SO4), and filtered. Evaporation under reduced pressure and
purification of the crude material by silica gel column chromatography
(petroleum ether/ethyl acetate) furnished the alcohol 3aa−3gh (68−
88%).
General Procedure for the Preparation of Z-Isomer (1,3-
Dihydroisobenzofurans 4): GP 2. To a solution of 2-(2-(alkyl-1-
yn-1-yl)phenyl)alkyl/phenyl-2-ol 1a−g (46−59 mg, 0.2 mmol) in dry
toluene (2 mL) were added arylbromide 2c−k (41−81 mg, 0.24
mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8 mg, 0.03 mmol), and
Cs2CO3 (130 mg, 0.4 mmol) under a nitrogen atmosphere. The
resultant reaction mixture was stirred at 80 °C (oil bath), for 4−6 h.
Completion of the reaction was monitored by TLC (5:95 ethyl
acetate and hexane). The reaction mixture was cooled to room
temperature and extracted with ethyl acetate (3 × 15 mL). The
combined organic layers were washed with brine solution, dried
(Na2SO4), and filtered. Evaporation under reduced pressure and
purification of the crude material by silica gel column chromatography
(petroleum ether/ethyl acetate) furnished the alcohol 4dd−4im (49−
88%).
cm−1. 1H NMR (400 MHz, CDCl3) δ 7.29−7.25 (m, 1H), 7.16−7.03
(m, 5H), 6.90 (ddd, J = 8.3, 7.0, 1.5 Hz, 1H), 6.27 (d, J = 7.9 Hz,
1H), 2.54 (t, J = 7.1 Hz, 2H), 2.36 (s, 3H), 1.57 (s, 6H), 1.42−1.33
(m, 4H), 1.27 (dd, J = 7.5, 3.6 Hz, 4H), 0.86 (t, J = 9.1 Hz, 3H) ppm.
13C{1H} NMR (100 MHz, CDCl3) δ 149.1, 149.0, 140.7, 138.1,
132.9, 130.6, 128.4, 127.4, 127.4, 127.1, 122.8, 120.1, 113.7, 85.0,
32.8, 31.8, 28.9, 28.5, 27.6, 22.7, 21.4, 14.1 ppm. HRMS (ESI) m/z:
[M + H]+ Calcd for C24H31O 335.2369; Found 335.2371.
(E)-1,1-Dimethyl-3-(1-(p-tolyl)heptylidene)-1,3-dihydroisobenzo-
furan (3ac). GP-1 was carried out with 2-(2-(oct-1-yn-1-yl)phenyl)-
propan-2-ol 1a (49 mg, 0.2 mmol), 4-bromotoluene 2c (41 mg, 0.24
mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8 mg, 0.03 mmol),
Cs2CO3 (130 mg, 0.4 mmol), and toluene (2 mL) at 100 °C, for 10 h.
Purification of the crude material by silica gel column chromatog-
raphy (petroleum ether/ethyl acetate, 100:0 to 98:2) furnished the
product 3ac (52 mg, 78%) as a colorless oil.
[TLC (petroleum ether/ethyl acetate 95:05, Rf (1a) = 0.3, Rf (3ac)
= 0.6, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax = 2892,
1
2824, 1708, 1444, 1251, 723 cm−1. H NMR (400 MHz, CDCl3) δ
7.23−7.07 (m, 6H), 6.94−6.88 (m, 1H), 6.31 (d, J = 7.9 Hz, 1H),
2.53 (t, J = 7.1 Hz, 2H), 2.41 (s, 3H), 1.57 (s, 6H), 1.36 (d, J = 1.9
Hz, 4H), 1.30−1.23 (m, 4H), 0.86 (t, J = 6.9 Hz, 3H) ppm. 13C{1H}
NMR (100 MHz, CDCl3) δ 149.0, 149.0, 137.7, 136.1, 132.9, 129.9,
129.3, 127.4, 127.0, 122.8, 120.1, 113.4, 85.0, 32.9, 31.8, 28.9, 28.5,
27.5, 22.7, 21.3, 14.1 ppm. HRMS (ESI) m/z: [M + H]+ Calcd for
C24H31O 335.2369; Found 335.2380.
(E)-1,1-Dimethyl-3-(1-(naphthalen-1-yl)heptylidene)-1,3-dihy-
droisobenzofuran (3ad). GP-1 was carried out with 2-(2-(oct-1-yn-
1-yl)phenyl)propan-2-ol 1a (49 mg, 0.2 mmol), 1-bromonaphthalene
2d (50 mg, 0.24 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8 mg,
0.03 mmol), Cs2CO3 (130 mg, 0.4 mmol), and toluene (2 mL) at 100
°C, for 8 h. Purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate, 100:0 to 98:2)
furnished the product 3ad (63 mg, 85%) as a colorless oil.
General Procedure for the Preparation of E-Isomer 3 from
Z-Isomer 4: GP 3. After recording the NMR spectra of Z-isomer 4 in
CDCl3, the same compound was kept aside in the NMR tube for 72 h.
During this period, conversion (geometrical isomerization) of Z-
isomer 4 into E-isomer 3 took place. This isomerization to E-isomeric
1
product 3 has been confirmed by measuring H NMR analysis.
X-ray Crystallographic Studies. A single crystal of compound
3gh was grown from hexane and CH2Cl2 at room temperature. For
compound 3gh, a crystal of suitable dimensions was mounted on a
CryoLoop (Hampton Research Corp.) with a layer of light mineral
oil. A single crystal of 3gh was selected and mounted on a Bruker
APEX-II CCD diffractometer. The crystal was kept at 298 K during
data collection. Using Olex2, the structure was solved with the
olex2.solve structure solution program using direct methods and
refined with the olex2. refinement package using Gauss−Newton
minimization. Absorption corrections were performed based on
multiple scans. Non-hydrogen atoms were anisotropically refined.
Hydrogen atoms were included in the refinement in the calculated
positions riding on their carrier atoms.
(E)-1,1-Dimethyl-3-(1-phenylheptylidene)-1,3-dihydroisobenzo-
furan (3aa). GP-1 was carried out with 2-(2-(oct-1-yn-1-yl)phenyl)-
propan-2-ol 1a (49 mg, 0.2 mmol), bromobenzene 2a (38 mg, 0.24
mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8 mg, 0.03 mmol),
Cs2CO3 (130 mg, 0.4 mmol), and toluene (2 mL) at 100 °C, for 10 h.
Purification of the crude material by silica gel column chromatog-
raphy (petroleum ether/ethyl acetate, 100:0 to 98:2) furnished the
product 3aa (52 mg, 82%) as a colorless oil.
[TLC (petroleum ether/ethyl acetate 95:05, Rf (1a) = 0.3, Rf (3ad)
= 0.6, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax = 3424,
3022, 2898, 2830, 1735, 1590, 1475, 1293, 1220,1077, 1027, 777,
1
725, 695 cm−1. H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.4 Hz,
1H), 7.88 (dd, J = 13.4, 8.2 Hz, 2H), 7.54−7.44 (m, 2H), 7.38 (td, J =
7.0, 3.4 Hz, 2H), 7.11−7.03 (m, 2H), 6.70 (ddd, J = 8.2, 6.8, 1.6 Hz,
1H), 5.74 (d, J = 7.9 Hz, 1H), 2.88 (dt, J = 13.2, 7.6 Hz, 1H), 2.44
(dt, J = 13.8, 6.9 Hz, 1H), 1.63 (d, J = 5.4 Hz, 6H), 1.44−1.34 (m,
4H), 1.29−1.24 (m, 4H), 0.86 (dd, J = 9.2, 4.9 Hz, 3H) ppm.
13C{1H} NMR (100 MHz, CDCl3) δ 150.0, 149.0, 138.3, 134.0,
132.7, 132.6, 128.2, 127.7, 127.4, 127.2, 125.9, 125.9, 125.7, 122.8,
120.0, 110.5, 85.3, 33.0, 31.8, 29.2, 28.6, 28.5, 27.9, 22.7, 14.1 ppm.
HRMS (ESI) m/z: [M + Na]+ Calcd for C27H30NaO 393.2189;
Found 393.2155.
(E)-3-(1-(4-Methoxyphenyl)heptylidene)-1,1-dimethyl-1,3-dihy-
droisobenzofuran (3ae). GP-3 was followed for the conversion of Z-
isomer 4ae to E-isomer 3ae (63 mg, 71%) as a colorless oil, in an
NMR tube in CDCl3 for 3 days.
[TLC (petroleum ether/ethyl acetate 95:05, Rf (1a) = 0.3, Rf (3aa)
= 0.6, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax = 2896,
1
2829, 2252, 1441, 1376, 1039, 918, 748 cm−1. H NMR (400 MHz,
IR (MIR-ATR, 4000−600 cm−1): νmax = 3409, 3023, 2896, 2829,
1733, 1589, 1474, 1444, 1291, 1218, 1076, 1024, 776 cm−1. 1H NMR
(400 MHz, CDCl3) δ 7.20−7.16 (m, 2H), 7.15−7.07 (m, 2H), 6.95−
6.90 (m, 3H), 6.30 (d, J = 7.9 Hz, 1H), 3.87 (s, 3H), 2.52 (t, J = 7.1
Hz, 2H), 1.56 (s, 6H), 1.36 (d, J = 3.4 Hz, 2H), 1.29−1.26 (m, 4H),
0.90−0.84 (m, 5H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 158.4,
149.1, 149.0, 133.1, 132.9, 131.1, 127.4, 127.1, 122.7, 120.2, 114.0,
113.0, 85.0, 55.2, 32.9, 31.8, 28.9, 28.5, 27.5, 22.7, 14.1 ppm. HRMS
(ESI) m/z: [M + H]+ Calcd for C24H31O2 351.2319; Found
351.2314.
(E)-1-Ethyl-1-methyl-3-(1-(m-tolyl)heptylidene)-1,3-dihydroiso-
benzofuran (3bb). GP-1 was carried out with 2-(2-(oct-1-yn-1-
yl)phenyl)butan-2-ol 1b (52 mg, 0.2 mmol), 3-bromotoluene 2b (41
mg, 0.24 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8 mg, 0.03
mmol), Cs2CO3 (130 mg, 0.4 mmol), and toluene (2 mL) at 100 °C,
for 12 h. Purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate, 100:0 to 98:2)
furnished the product 3bb (52 mg, 74%) as a colorless oil.
CDCl3) δ 7.42−7.35 (m, 2H), 7.33 (dt, J = 5.2, 2.1 Hz, 1H), 7.30−
7.26 (m, 2H), 7.18−7.07 (m, 2H), 6.95−6.84 (m, 1H), 6.24 (d, J =
7.9 Hz, 1H), 2.55 (t, J = 7.1 Hz, 2H), 1.57 (s, 6H), 1.41−1.25 (m,
8H), 0.86 (t, J = 7.0 Hz, 3H) ppm. 13C{1H} NMR (100 MHz,
CDCl3) δ 149.0, 140.8, 132.7, 130.1, 128.6, 127.5, 127.1, 126.6, 122.7,
120.2, 113.5, 85.1, 32.8, 31.8, 28.9, 28.5, 27.5, 22.7, 14.1 ppm. HRMS
(ESI) m/z: [M + H]+ Calcd for C23H29O 321.2213; Found 321.2209.
(E)-1,1-Dimethyl-3-(1-(m-tolyl)heptylidene)-1,3-dihydroisoben-
zofuran (3ab). GP-1 was carried out with 2-(2-(oct-1-yn-1-
yl)phenyl)propan-2-ol 1a (49 mg, 0.2 mmol), 3-bromotoluene 2b
(41 mg, 0.24 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8 mg, 0.03
mmol), Cs2CO3 (130 mg, 0.4 mmol), and toluene (2 mL) at 100 °C,
for 10 h. Purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate, 100:0 to 98:2)
furnished the product 3ab (51 mg, 77%) as a colorless oil.
[TLC (petroleum ether/ethyl acetate 95:05, Rf (1a) = 0.3, Rf (3ab)
= 0.6, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax = 3434,
3003, 2926, 2893, 2827, 1747, 1444, 1359, 1081, 1018, 752, 704
8191
https://doi.org/10.1021/acs.joc.1c00666
J. Org. Chem. 2021, 86, 8182−8196

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
[TLC (petroleum ether/ethyl acetate 95:05, Rf (1b) = 0.3, Rf
127.2, 122.7, 122.5, 120.3, 112.0, 85.4, 32.7, 31.9, 29.5, 29.3, 29.2,
28.4, 27.5, 22.7, 14.1 ppm. HRMS (ESI) m/z: [M + H]+ Calcd for
C25H32Br79O 427.1631; Found 427.1624. HRMS (ESI) m/z: [M +
H]+ Calcd for C25H32Br81O 429.1611; Found: 429.1606.
(3bb) = 0.6, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax
=
3032, 2892, 2825, 1747, 1573, 1497, 1443, 1322, 1076, 1047, 845,
1
747, 689 cm−1. H NMR (400 MHz, CDCl3) δ 7.30 (t, J = 7.5 Hz,
1H), 7.13 (ddd, J = 24.3, 15.5, 7.4 Hz, 5H), 6.98−6.90 (m, 1H), 6.34
(d, J = 7.9 Hz, 1H), 2.65 (dd, J = 13.8, 6.9 Hz, 1H), 2.53 (dt, J = 13.7,
6.9 Hz, 1H), 2.40 (s, 3H), 1.97 (dt, J = 14.7, 7.3 Hz, 1H), 1.91−1.82
(m, 1H), 1.57 (s, 3H), 1.47−1.39 (m, 4H), 1.34−1.30 (m, 4H), 0.91
(t, J = 6.9 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H) ppm. 13C{1H} NMR (100
MHz, CDCl3) δ 149.7, 147.6, 140.8, 138.1, 133.8, 130.6, 128.4, 127.3,
127.2, 127.1, 122.7, 120.4, 113.1, 87.5, 34.4, 32.9, 31.8, 29.0, 27.6,
26.8, 22.7, 21.4, 14.1, 8.1 ppm. HRMS (ESI) m/z: [M + H]+ Calcd
for C25H33O 349.2526; Found 349.2526.
(E)-1-Ethyl-1-methyl-3-(1-(p-tolyl)heptylidene)-1,3-dihydroiso-
benzofuran (3bc). GP-1 was carried out with 2-(2-(oct-1-yn-1-
yl)phenyl)butan-2-ol 1b (52 mg, 0.2 mmol), 4-bromotoluene 2c (41
mg, 0.24 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8 mg, 0.03
mmol), Cs2CO3 (130 mg, 0.4 mmol), and toluene (2 mL) at 100 °C,
for 12 h. Purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate, 100:0 to 98:2)
furnished the product 3bc (55 mg, 79%) as a colorless oil.
(E)-1,1-Dimethyl-3-(1-(naphthalen-1-yl)nonylidene)-1,3-dihy-
droisobenzofuran (3cd). GP-1 was carried out with 2-(2-(dec-1-yn-
1-yl)phenyl)propan-2-ol 1c (54 mg, 0.2 mmol), 1-bromonaphatha-
lene 2d (50 mg, 0.24 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8
mg, 0.03 mmol), Cs2CO3 (130 mg, 0.4 mmol), and toluene (2 mL) at
100 °C, for 12 h. Purification of the crude material by silica gel
column chromatography (petroleum ether/ethyl acetate, 100:0 to
98:2) furnished the product 3cd (70 mg, 88%) as a colorless oil.
[TLC (petroleum ether/ethyl acetate 95:05, Rf (1c) = 0.3, Rf (3cd)
= 0.6, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax = 2892,
1
2823, 1642, 1446, 1320, 1132, 1079, 770, 749 cm−1. H NMR (400
MHz, CDCl3) δ 8.00 (d, J = 8.4 Hz, 1H), 7.88 (dd, J = 13.3, 8.1 Hz,
2H), 7.56−7.43 (m, 2H), 7.39 (t, J = 6.9 Hz, 2H), 7.13−7.02 (m,
2H), 6.74−6.65 (m, 1H), 5.74 (d, J = 7.9 Hz, 1H), 2.94−2.83 (m,
1H), 2.44 (dt, J = 13.7, 6.7 Hz, 1H), 1.63 (d, J = 5.2 Hz, 6H), 1.39
(dd, J = 13.0, 6.6 Hz, 4H), 1.26 (d, J = 14.5 Hz, 8H), 0.86 (t, J = 6.7
Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 150.0, 149.0,
138.3, 134.0, 132.6, 132.6, 128.2, 127.7, 127.4, 127.2, 125.9, 125.9,
125.7, 122.8, 120.0, 110.5, 85.3, 32.9, 31.9, 29.5, 29.5, 29.4, 28.6, 28.5,
27.9, 22.7, 14.12 ppm. HRMS (ESI) m/z: [M + H]+ Calcd for
C29H35O 399.2682; Found: 399.2673.
(E)-1,1-Dimethyl-3-(1-(p-tolyl)hexylidene)-1,3-dihydroisobenzo-
furan (3dc). GP-1 was carried out with 2-(2-(hept-1-yn-1-yl)phenyl)-
propan-2-ol 1d (46 mg, 0.2 mmol), 4-bromotoluene 2c (41 mg, 0.24
mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8 mg, 0.03 mmol),
Cs2CO3 (130 mg, 0.4 mmol), and toluene (2 mL) at 100 °C, for 12 h.
Purification of the crude material by silica gel column chromatog-
raphy (petroleum ether/ethyl acetate, 100:0 to 98:2) furnished the
product 3dc (48 mg, 75%) as a colorless oil.
[TLC (petroleum ether/ethyl acetate 95:05, Rf (1b) = 0.3, Rf (3bc)
= 0.6, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax = 3428,
1
2896, 2833, 1740, 1663, 1441, 1357, 1010, 800, 753, 711 cm−1. H
NMR (400 MHz, CDCl3) δ 7.22−7.12 (m, 5H), 7.06 (d, J = 7.4 Hz,
1H), 6.95−6.89 (m, 1H), 6.34 (d, J = 7.9 Hz, 1H), 2.62 (dt, J = 14.3,
7.1 Hz, 1H), 2.50 (dd, J = 13.2, 7.0 Hz, 1H), 2.42 (s, 3H), 1.95 (dd, J
= 14.1, 7.3 Hz, 1H), 1.83 (dd, J = 14.1, 7.3 Hz, 1H), 1.55 (s, 3H),
1.44−1.35 (m, 4H), 1.32−1.26 (m, 4H), 0.88 (t, J = 6.8 Hz, 3H),
0.82 (t, J = 7.4 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ
149.7, 147.6, 137.8, 136.1, 133.8, 129.9, 129.3, 127.3, 127.0, 122.6,
120.4, 112.8, 87.5, 34.4, 33.0, 31.8, 29.0, 27.6, 26.8, 22.7, 21.3, 14.1,
8.1 ppm. HRMS (ESI) m/z: [M + H]+ Calcd for C25H33O 349.2526;
Found 349.2521.
(E)-1,1-Dimethyl-3-(1-phenylnonylidene)-1,3-dihydroisobenzo-
furan (3ca). GP-1 was carried out with 2-(2-(dec-1-yn-1-yl)phenyl)-
propan-2-ol 1c (54 mg, 0.2 mmol), bromobenzene 2a (38 mg, 0.24
mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8 mg, 0.03 mmol),
Cs2CO3 (130 mg, 0.4 mmol), and toluene (2 mL) at 100 °C, for 12 h.
Purification of the crude material by silica gel column chromatog-
raphy (petroleum ether/ethyl acetate, 100:0 to 98:2) furnished the
product 3ca (54 mg, 77%) as a colorless oil.
[TLC (petroleum ether/ethyl acetate 95:05, Rf (1d) = 0.3, Rf
(3dc) = 0.6, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax
=
2995, 2893, 2833, 1585, 1477, 1447, 1165, 1067, 1023, 759, 718, 683
cm−1. 1H NMR (400 MHz, CDCl3) δ 7.22−7.08 (m, 6H), 6.92 (ddd,
J = 8.3, 7.0, 1.5 Hz, 1H), 6.32 (d, J = 7.9 Hz, 1H), 2.58−2.52 (m,
2H), 2.42 (s, 3H), 1.58 (s, 6H), 1.42−1.31 (m, 6H), 0.87 (t, J = 7.1
Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 149.0, 149.0,
137.7, 136.1, 132.9, 129.9, 129.3, 127.4, 127.0, 122.8, 120.1, 113.4,
85.0, 32.8, 31.4, 28.5, 27.2, 22.6, 21.3, 14.1 ppm. HRMS (ESI) m/z:
[M + H]+ Calcd for C23H29O 321.2213; Found: 321.2198.
(E)-1-Methyl-1-propyl-3-(1-(p-tolyl)hexylidene)-1,3-dihydroiso-
benzofuran (3ec). GP-3 was followed for the conversion of Z-isomer
4ec to E-isomer 3ec (48 mg, 69%) as a colorless oil, in an NMR tube
in CDCl3 for 3 days.
[TLC (petroleum ether/ethyl acetate 95:05, Rf (1c) = 0.3, Rf (3ca)
= 0.6, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax = 2993,
2892, 2824, 1640, 1446, 1228, 1133, 1083, 896, 747, 697, 647 cm−1
.
1H NMR (400 MHz, CDCl3) δ = 7.39 (ddd, J = 7.4, 4.4, 1.3 Hz, 2H),
7.35−7.30 (m, 1H), 7.30−7.25 (m, 2H), 7.18−7.07 (m, 2H), 6.89
(ddd, J = 8.3, 6.9, 1.5 Hz, 1H), 6.24 (d, J = 7.9 Hz, 1H), 2.55 (t, J =
7.1 Hz, 2H), 1.57 (s, 6H), 1.38 (dd, J = 6.6, 5.0 Hz, 4H), 1.26 (d, J =
13.6 Hz, 8H), 0.86 (t, J = 6.8 Hz, 3H) ppm. 13C NMR (100 MHz,
CDCl3) δ = 149.1, 140.8, 132.8, 130.1, 128.6, 127.5, 127.1, 126.6,
122.7, 120.2, 113.5, 85.1, 32.8, 31.9, 29.5, 29.4, 29.2, 28.5, 27.5, 22.7,
14.1 ppm. HRMS (ESI) m/z: [M + H]+ Calcd for C25H33O
349.2526; Found 349.2511.
(E)-3-(1-(3-Bromophenyl)nonylidene)-1,1-dimethyl-1,3-dihydroi-
sobenzofuran (3cg). GP-1 was carried out with 2-(2-(dec-1-yn-1-
yl)phenyl)propan-2-ol 1c (54 mg, 0.2 mmol), 1,3-dibromobenzene 2g
(57 mg, 0.24 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8 mg, 0.03
mmol), Cs2CO3 (130 mg, 0.4 mmol), and toluene (2 mL) at 100 °C,
for 12 h. Purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate, 100:0 to 98:2)
furnished the product 3cg (63 mg, 74%) as a colorless oil.
IR (MIR-ATR, 4000−600 cm−1): νmax = 2927, 2897, 2839, 1744,
1
1444, 1358, 1253, 1090, 1010, 727, 694 cm−1. H NMR (400 MHz,
CDCl3) δ 7.20−7.11 (m, 5H), 7.08−7.04 (m, 1H), 6.94−6.88 (m,
1H), 6.32 (d, J = 7.9 Hz, 1H), 2.58 (dd, J = 14.0, 6.9 Hz, 1H), 2.52−
2.43 (m, 1H), 2.41 (s, 3H), 1.89 (ddd, J = 13.8, 11.7, 4.8 Hz, 1H),
1.76 (ddd, J = 13.8, 11.7, 4.7 Hz, 1H), 1.53 (s, 3H), 1.43−1.30 (m,
7H), 1.16−1.02 (m, 1H), 0.87 (dd, J = 9.9, 4.8 Hz, 6H) ppm.
13C{1H} NMR (100 MHz, CDCl3) δ 149.6, 148.0, 137.8, 136.1,
133.6, 129.9, 129.3, 127.3, 127.0, 122.7, 120.4, 112.9, 87.3, 43.9, 32.9,
31.5, 27.3, 27.1, 22.6, 21.3, 17.0, 14.3, 14.1 ppm. HRMS (ESI) m/z:
[M + H]+ Calcd for C25H33O 349.2526; Found: 349.2494.
(E)-6-Methoxy-1,1-dimethyl-3-(1-(naphthalen-1-yl)hexylidene)-
1,3-dihydroisobenzofuran (3fd). GP-1 was carried out with 2-(2-
(hept-1-yn-1-yl)-5-methoxyphenyl)propan-2-ol 1f (52 mg, 0.2
mmol), 1-bromonaphthalene 2d (50 mg, 0.24 mmol), Pd(OAc)2 (2
mg, 0.01 mmol), PPh3 (8 mg, 0.03 mmol), Cs2CO3 (130 mg, 0.4
mmol), and toluene (2 mL) at 100 °C, for 12 h. Purification of the
crude material by silica gel column chromatography (petroleum
ether/ethyl acetate, 100:0 to 95:05) furnished the product 3fd (66
mg, 85%) as a colorless oil.
[TLC (petroleum ether/ethyl acetate 95:05, Rf (1c) = 0.3, Rf (3cg)
= 0.6, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax = 2893,
1
2825, 1639, 1449, 1259, 1131, 1083, 745, 698 cm−1. H NMR (400
MHz, CDCl3) δ 7.49−7.43 (m, 2H), 7.26−7.19 (m, 2H), 7.16 (d, J =
7.3 Hz, 1H), 7.14−7.09 (m, 1H), 6.95 (dd, J = 11.1, 4.0 Hz, 1H), 6.33
(d, J = 7.9 Hz, 1H), 2.52 (t, J = 6.7 Hz, 2H), 1.57 (s, 6H), 1.36−1.24
(m, 12H), 0.87 (t, J = 6.7 Hz, 3H) ppm. 13C{1H} NMR (100 MHz,
CDCl3) δ 149.6, 149.2, 143.1, 133.0, 132.3, 130.1, 129.7, 128.9, 127.8,
[TLC (petroleum ether/ethyl acetate 90:10, Rf (1f) = 0.5, Rf (3fd)
= 0.4, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax = 3021,
2897, 2830, 1732, 1590, 1473, 1291, 1218, 1076, 1022, 777, 688
8192
https://doi.org/10.1021/acs.joc.1c00666
J. Org. Chem. 2021, 86, 8182−8196

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
cm−1. 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.3 Hz, 1H), 7.87
(dd, J = 16.1, 8.1 Hz, 2H), 7.53−7.44 (m, 2H), 7.41−7.36 (m, 2H),
6.59 (d, J = 2.3 Hz, 1H), 6.26 (dd, J = 8.7, 2.4 Hz, 1H), 5.63 (d, J =
8.6 Hz, 1H), 3.68 (s, 3H), 2.84 (dt, J = 13.4, 7.6 Hz, 1H), 2.43 (dt, J =
13.8, 6.8 Hz, 1H), 1.62 (d, J = 5.5 Hz, 6H), 1.37−1.27 (m, 6H), 0.86
(d, J = 7.0 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 159.5,
150.9, 149.8, 138.6, 134.1, 132.8, 128.2, 127.9, 127.0, 126.0, 125.9,
125.8, 125.7, 125.4, 123.9, 113.3, 108.2, 105.4, 85.0, 55.3, 32.7, 31.7,
28.5, 28.4, 27.6, 22.6, 14.1 ppm. HRMS (ESI) m/z: [M + H]+ Calcd
for C27H31O2 387.2319; Found 387.2316.
(E)-1-(4-(1-(5-Methoxy-3,3-dimethylisobenzofuran-1(3H)-
ylidene)hexyl)phenyl)ethan-1-one (3fi). GP-1 was carried out with
2-(2-(hept-1-yn-1-yl)-5-methoxyphenyl)propan-2-ol 1f (52 mg, 0.2
mmol), 4-bromoacetophenone 2i (48 mg, 0.24 mmol), Pd(OAc)2 (2
mg, 0.01 mmol), PPh3 (8 mg, 0.03 mmol), Cs2CO3 (130 mg, 0.4
mmol), and toluene (2 mL) at 100 °C, for 12 h. Purification of the
crude material by silica gel column chromatography (petroleum
ether/ethyl acetate, 100:0 to 90:10) furnished the product 3fi (54 mg,
71%) as a colorless oil.
GP-3 was followed for the conversion of Z-isomer 4gh to E-isomer
3gh (69 mg, 76%) as a colorless solid, in an NMR tube in CDCl3 for 3
days.
Mp: 129−131 °C; IR (MIR-ATR, 4000−600 cm−1): νmax = 3030,
2940, 2893, 2827, 2205, 1741, 1609, 1579, 1484, 1446, 1371, 1245,
1
1191, 1153, 1047, 1012, 843, 806, 749 cm−1. H NMR (400 MHz,
CDCl3) δ 7.80−7.67 (m, 5H), 7.62 (d, J = 8.3 Hz, 2H), 7.57 (s, 1H),
7.28−7.21 (m, 2H), 7.08 (dd, J = 6.4, 0.9 Hz, 2H), 6.73 (ddd, J = 8.3,
6.4, 2.1 Hz, 1H), 5.80 (d, J = 7.9 Hz, 1H), 5.26 (s, 2H), 2.36 (tt, J =
8.4, 5.3 Hz, 1H), 1.63 (s, 6H), 0.67 (d, J = 8.4 Hz, 2H), 0.29 (d, J =
8.4 Hz 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 156.2, 149.9,
148.5, 142.4, 133.4, 132.8, 132.4, 131.9, 130.5, 129.9, 129.8, 129.4,
127.6, 127.6, 127.3, 127.2, 127.0, 122.4, 120.2, 118.7, 113.2, 111.7,
107.0, 85.5, 68.9, 28.6, 12.5, 3.8 ppm. HRMS (ESI) m/z: [M + K]+
Calcd for C32H27KNO2 496.1673; Found 496.1647.
(E)-6-Chloro-1,1-dimethyl-3-(1-phenylheptylidene)-1,3-dihydroi-
sobenzofuran (3ka). GP-3 was followed for the conversion of Z-
isomer 4ka to E-isomer 3ka (52 mg, 73%) as a colorless liquid, in an
NMR tube in CDCl3 for 3 days.
IR (MIR-ATR, 4000−600 cm−1): νmax = 2894, 2827, 1641, 1444,
1272, 1136, 1094, 1001, 816, 763 cm−1. 1H NMR (400 MHz, CDCl3)
δ 7.40−7.35 (m, 2H), 7.34−7.31 (m, 1H), 7.25−7.21 (m, 2H), 7.05
(d, J = 1.6 Hz, 1H), 6.84 (dd, J = 8.4, 1.9 Hz, 1H), 6.11 (d, J = 8.4 Hz,
1H), 2.52 (t, J = 7.1 Hz, 2H), 1.55 (s, 6H), 1.35 (dd, J = 4.2, 2.9 Hz,
4H), 1.27−1.23 (m, 4H), 0.85 (t, J = 5.3 Hz, 3H) ppm. 13C NMR
(100 MHz, CDCl3) δ = 150.8, 148.2, 140.5, 133.2, 131.4, 129.9,
128.7, 127.5, 126.8, 123.8, 120.6, 114.3, 84.8, 32.8, 31.8, 28.9, 28.4,
27.4, 22.7, 14.1 ppm. HRMS (ESI) m/z: [M + K]+ Calcd for
C23H27ClKO 393.1382; Found 393.1405.
(Z)-1,1-Dimethyl-3-(1-(naphthalen-1-yl)hexylidene)-1,3-dihy-
droisobenzofuran (4dd). GP-2 was carried out with 2-(2-(hept-1-yn-
1-yl)phenyl)propan-2-ol 1d (46 mg, 0.2 mmol), 1-bromonaphthalene
2d (50 mg, 0.24 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8 mg,
0.03 mmol), Cs2CO3 (130 mg, 0.4 mmol), and toluene (2 mL) at 80
°C, for 5 h. Purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate, 100:0 to 98:02)
furnished the product 4dd (60 mg, 84%) as a colorless oil.
[TLC (petroleum ether/ethyl acetate 90:10, Rf (1f) = 0.5, Rf (3fi)
= 0.3, UV detection]. Major isomer NMR data (3fi:4fi = 4.3:1): IR
(MIR-ATR, 4000−600 cm−1): νmax = 2894, 2829, 1660, 1390, 1345,
1250, 948, 827, 722 cm−1. 1H NMR (400 MHz, CDCl3) δ 8.00−7.95
(m, 2H), 7.44−7.35 (m, 2H), 6.62 (d, J = 2.3 Hz, 1H), 6.48 (dd, J =
8.7, 2.4 Hz, 1H), 6.34 (d, J = 8.7 Hz, 1H), 3.76 (s, 3H), 2.65 (s, 3H),
2.55 (t, J = 7.2 Hz, 2H), 1.57 (s, 6H), 1.38−1.30 (m, 6H), 0.85 (t, J =
7.0 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 198.0, 159.9,
151.4, 149.5, 146.9, 135.3, 130.4, 128.7, 125.0, 123.7, 113.4, 110.3,
105.5, 85.1, 55.4, 32.3, 31.3, 28.3, 27.5, 26.6, 22.5, 14.1 ppm. HRMS
(ESI) m/z: [M + H]+ Calcd for C25H31O3 379.2268; Found:
379.2267.
(E)-4-(1-(5-Methoxy-3,3-dimethylisobenzofuran-1(3H)-ylidene)-
hexyl)benzaldehyde (3fl). GP-1 was carried out with 2-(2-(hept-1-
yn-1-yl)-5-methoxyphenyl)propan-2-ol 1f (52 mg, 0.2 mmol), 4-
bromobenzaldehyde 2l (44 mg, 0.24 mmol), Pd(OAc)2 (2 mg, 0.01
mmol), PPh3 (8 mg, 0.03 mmol), Cs2CO3 (130 mg, 0.4 mmol), and
toluene (2 mL) at 100 °C, for 12 h. Purification of the crude material
by silica gel column chromatography (petroleum ether/ethyl acetate,
100:0 to 90:10) furnished the product 3fl (50 mg, 68%) as a colorless
oil.
[TLC (petroleum ether/ethyl acetate 95:05, Rf (1d) = 0.3, Rf
(4dd) = 0.6, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax
=
3435, 2896, 2833, 1741, 1644, 1442, 1357, 1262, 1174, 1081, 1009,
1
912, 799, 750 cm−1. H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.4
[TLC (petroleum ether/ethyl acetate 90:10, Rf (1f) = 0.5, Rf (3fl)
= 0.3, UV detection]. Major isomer NMR data (3fl:4fl = 2:1): IR
(MIR-ATR, 4000−600 cm−1): νmax = 3426, 2894, 2828, 1745, 1663,
Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.80 (dd, J = 10.4, 8.0 Hz, 2H),
7.55−7.49 (m, 1H), 7.48−7.33 (m, 5H), 7.21 (d, J = 7.3 Hz, 1H),
2.91−2.73 (m, 2H), 1.57 (dd, J = 13.4, 9.9 Hz, 2H), 1.37 (d, J = 11.8
Hz, 6H), 1.35−1.22 (m, 4H), 0.85 (t, J = 7.1 Hz, 3H) ppm. 13C{1H}
NMR (100 MHz, CDCl3) δ 150.1, 149.5, 140.5, 133.7, 132.8, 131.7,
128.1, 128.0, 127.8, 126.8, 126.5, 126.2, 125.5, 125.3, 125.0, 123.2,
120.7, 110.7, 85.1, 33.2, 32.0, 28.7, 28.5, 28.0, 22.6, 14.1 ppm. HRMS
(ESI) m/z: [M + K]+ Calcd for C26H28KO 395.1772; Found
395.1774.
(Z)-1-(4-(1-(3,3-Dimethylisobenzofuran-1(3H)-ylidene)heptyl)-
phenyl)ethan-1-one (4ai). GP-2 was carried out with 2-(2-(oct-1-yn-
1-yl)phenyl)propan-2-ol 1a (52 mg, 0.2 mmol), 4-bromoacetophe-
none 2i (48 mg, 0.24 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8
mg, 0.03 mmol), Cs2CO3 (130 mg, 0.4 mmol), and toluene (2 mL) at
80 °C, for 6 h. Purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate, 100:0 to 95:05)
furnished the product 4ai (57 mg, 79%) as a colorless oil.
1
1584, 1445, 1345, 1252, 1079, 1026, 945, 751, 692 cm−1. H NMR
(400 MHz, CDCl3) δ 10.04 (s, 1H), 7.92−7.86 (m, 2H), 7.53−7.44
(m, 2H), 6.63 (d, J = 2.3 Hz, 1H), 6.49 (dd, J = 8.7, 2.4 Hz, 1H), 6.36
(d, J = 8.7 Hz, 1H), 3.76 (s, 3H), 2.61−2.53 (m, 2H), 1.57 (s, 6H),
1.38−1.31 (m, 6H), 0.85 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR
(100 MHz, CDCl3) δ 192.0, 160.0, 151.5, 149.8, 148.5, 134.7, 130.9,
130.0, 125.0, 123.7, 113.5, 110.2, 105.5, 85.3, 55.4, 32.3, 31.3, 28.3,
27.5, 22.5, 14.1 ppm. HRMS (ESI) m/z: [M + H]+ Calcd for
C24H29O3 365.2111; Found 365.2115.
(E)-3-(Cyclopropyl(naphthalen-1-yl)methylene)-1,1-dimethyl-
1,3-dihydroisobenzofuran (3gd). GP-3 was followed for the
conversion of Z-isomer 4gd to E-isomer 3gd (54 mg, 83%) as a
colorless oil, in an NMR tube in CDCl3 for 3 days.
IR (MIR-ATR, 4000−600 cm−1): νmax = 2896, 2829, 1733, 1664,
1
1589, 1474, 1291, 1218, 1075, 1021, 777, 688 cm−1. H NMR (400
[TLC (petroleum ether/ethyl acetate 90:10, Rf (1a) = 0.6, Rf (4ai)
= 0.4, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax = 3429,
2894, 2829, 1744, 1663, 1585, 1445, 1346, 1252, 1022, 945, 897, 837,
MHz, CDCl3) δ 8.02 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 8.2 Hz, 2H),
7.46 (ddd, J = 9.3, 8.1, 4.1 Hz, 2H), 7.42−7.36 (m, 1H), 7.26 (s, 1H),
7.08 (d, J = 7.4 Hz, 1H), 7.06−6.98 (m, 1H), 6.69−6.59 (m, 1H),
5.44 (d, J = 7.9 Hz, 1H), 2.49 (ddd, J = 10.6, 6.8, 4.2 Hz, 1H), 1.66 (s,
6H), 0.77−0.64 (m, 1H), 0.62−0.50 (m, 1H), 0.35 (td, J = 9.4, 5.3
Hz, 1H), −0.08 (td, J = 9.9, 5.5 Hz, 1H) ppm. 13C{1H} NMR (100
MHz, CDCl3) δ 150.5, 148.4, 133.8, 133.7, 133.6, 132.6, 128.9, 128.0,
127.7, 127.3, 127.2, 126.1, 126.0, 125.8, 125.6, 122.4, 120.0, 110.6,
85.5, 28.9, 28.5, 12.8, 4.4, 4.0 ppm. HRMS (ESI) m/z: [M + K]+
Calcd for C24H22KO 365.1302; Found 365.1294.
1
751, 692 cm−1. H NMR (400 MHz, CDCl3) δ 7.97−7.92 (m, 2H),
7.74−7.70 (m, 2H), 7.69−7.66 (m, 1H), 7.37 (ddd, J = 6.9, 5.2, 1.3
Hz, 2H), 7.23 (dd, J = 6.5, 2.0 Hz, 1H), 2.83−2.76 (m, 2H), 2.61 (s,
3H), 1.59−1.52 (m, 8H), 1.46−1.38 (m, 2H), 1.30 (td, J = 7.0, 3.6
Hz, 4H), 0.88 (t, J = 7.0 Hz, 3H) ppm. 13C{1H} NMR (100 MHz,
CDCl3) δ 197.8, 151.2, 149.9, 146.8, 134.0, 132.9, 128.6, 128.5, 128.0,
128.0, 123.7, 120.7, 111.4, 86.0, 31.7, 30.7, 29.4, 29.2, 28.3, 26.5, 22.6,
14.0 ppm. HRMS (ESI) m/z: [M + H]+ Calcd for C25H31O2
363.2319; Found 363.2324.
(E)-4-(((6-(Cyclopropyl(3,3-dimethylisobenzofuran-1(3H)-
ylidene)methyl)naphthalen-2-yl)oxy)methyl)benzonitrile (3gh).
8193
https://doi.org/10.1021/acs.joc.1c00666
J. Org. Chem. 2021, 86, 8182−8196

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(Z)-3-(1-(4-Methoxyphenyl)heptylidene)-1,1-dimethyl-1,3-dihy-
droisobenzofuran (4ae). GP-2 was carried out with 2-(2-(oct-1-yn-1-
yl)phenyl)propan-2-ol 1a (52 mg, 0.2 mmol), 4-bromoanisole 2e (45
mg, 0.24 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8 mg, 0.03
mmol), Cs2CO3 (130 mg, 0.4 mmol), and toluene (2 mL) at 80 °C,
for 4 h. Purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate, 100:0 to 95:05)
furnished the product 4ae (50 mg, 71%) as a colorless oil.
7.52 (d, J = 8.1 Hz, 2H), 7.38−7.31 (m, 2H), 7.18 (d, J = 8.4 Hz,
3H), 2.80−2.73 (m, 2H), 2.38 (s, 3H), 1.88 (ddd, J = 13.8, 11.8, 4.8
Hz, 1H), 1.79−1.70 (m, 1H), 1.63−1.56 (m, 2H), 1.50 (s, 3H), 1.39
(tdd, J = 11.2, 8.7, 3.5 Hz, 6H), 0.92 (t, J = 7.0 Hz, 3H), 0.84 (t, J =
7.3 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 149.9, 148.6,
138.6, 134.9, 134.2, 128.5, 128.4, 127.7, 127.7, 123.2, 120.8, 111.9,
87.5, 43.7, 32.0, 31.2, 28.9, 27.1, 22.6, 21.2, 17.1, 14.3, 14.1 ppm.
HRMS (ESI) m/z: [M + H]+ Calcd for C25H33O 349.2526; Found
349.2505.
(Z)-1-Methyl-3-(1-(4-nitrophenyl)heptylidene)-1-phenyl-1,3-di-
hydroisobenzofuran (4hj). GP-2 was carried out with 1-(2-(oct-1-yn-
1-yl)phenyl)-1-phenylethan-1-ol 1h (61 mg, 0.2 mmol), 1-bromo-4-
nitrobenzene 2j (48 mg, 0.24 mmol), Pd(OAc)2 (2 mg, 0.01 mmol),
PPh3 (8 mg, 0.03 mmol), Cs2CO3 (130 mg, 0.4 mmol), and toluene
(2 mL) at 80 °C, for 6 h. Purification of the crude material by silica
gel column chromatography (petroleum ether/ethyl acetate, 100:0 to
90:10) furnished the product 4hj (65 mg, 76%) as a pale-yellow oil.
[TLC (petroleum ether/ethyl acetate 85:15, Rf (1h) = 0.7, Rf (4hj)
= 0.5, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax = 2891,
2824, 1748, 1573, 1498, 1444, 1323, 1257, 1178, 1125, 1076, 1047,
1016, 846, 748, 689 cm−1. 1H NMR (400 MHz, CDCl3) δ 8.26−8.12
(m, 2H), 7.82−7.75 (m, 2H), 7.73 (d, J = 7.5 Hz, 1H), 7.43−7.35 (m,
4H), 7.32−7.27 (m, 3H), 7.25 (t, J = 3.6 Hz, 1H), 2.89−2.79 (m,
2H), 1.93 (s, 3H), 1.60 (dd, J = 11.0, 5.1 Hz, 2H), 1.43 (dd, J = 9.4,
5.4 Hz, 2H), 1.35−1.27 (m, 4H), 0.89 (t, J = 7.1 Hz, 3H) ppm.
13C{1H} NMR (100 MHz, CDCl3) δ 152.3, 149.1, 148.4, 145.2,
[TLC (petroleum ether/ethyl acetate 90:10, Rf (1a) = 0.6, Rf (4ae)
= 0.5, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax = 2928,
2860, 1762, 1677, 1603, 1507, 1460, 1288, 1246, 1174, 1036, 831,
1
762 cm−1. H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.8 Hz, 1H),
7.62−7.56 (m, 2H), 7.40−7.31 (m, 2H), 7.24−7.21 (m, 1H), 6.96−
6.91 (m, 2H), 3.86 (s, 3H), 2.79 (dd, J = 8.8, 7.5 Hz, 2H), 1.57 (s,
6H), 1.39 (ddd, J = 11.1, 10.5, 5.5 Hz, 8H), 0.93−0.90 (m, 3H) ppm.
13C{1H} NMR (100 MHz, CDCl3) δ 157.3, 149.5, 148.9, 133.7,
133.4, 129.7, 127.8, 127.7, 123.2, 120.6, 113.1, 112.1, 85.1, 55.1, 31.7,
31.3, 29.4, 29.1, 28.4, 22.6, 14.1 ppm. HRMS (ESI) m/z: [M + Na]+
Calcd for C25H31O2 363.2138; Found 363.2102.
(Z)-2-(1-(3,3-Dimethylisobenzofuran-1(3H)-ylidene)heptyl)-
benzaldehyde (4af). GP-2 was carried out with 2-(2-(oct-1-yn-1-
yl)phenyl)propan-2-ol 1a (52 mg, 0.2 mmol), 2-bromobenzaldehyde
2f (44 mg, 0.24 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8 mg,
0.03 mmol), Cs2CO3 (130 mg, 0.4 mmol), and toluene (2 mL) at 80
°C, for 6 h. Purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate, 100:0 to 95:05)
furnished the product 4af (53 mg, 76%) as a colorless oil.
143.9, 132.4, 129.1, 129.1, 128.5, 128.4, 127.6, 125.0, 123.9, 123.2,
122.2, 111.2, 89.0, 31.6, 30.6, 29.3, 29.2, 27.6, 22.6, 14.0 ppm. HRMS
(ESI) m/z: [M + H]+ Calcd for C28H30NO3 428.2220; Found
428.2227.
[TLC (petroleum ether/ethyl acetate 90:10, Rf (1a) = 0.6, Rf (4af)
= 0.5, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax = 2892,
2797, 2705, 1673, 1587, 1288, 1197, 1155, 836, 798, 747, 722 cm−1
.
1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 7.94 (dd, J = 7.7, 1.3
(Z)-1,1-Diphenyl-3-(1-(m-tolyl)heptylidene)-1,3-dihydroisoben-
zofuran (4lb). GP-2 was carried out with (2-(oct-1-yn-1-yl)phenyl)-
diphenylmethanol 1l (74 mg, 0.2 mmol), 1-bromo-3-methylbenzene
2b (41 mg, 0.24 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8 mg,
0.03 mmol), Cs2CO3 (130 mg, 0.4 mmol), and toluene (2 mL) at 80
°C, for 6 h. Purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate, 100:0 to 90:10)
furnished the product 4lb (77 mg, 84%) as a pale-yellow oil.
[TLC (petroleum ether/ethyl acetate 85:15, Rf (1l) = 0.7, Rf (4lb)
= 0.5, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax = 2892,
2824, 2705, 1640, 1446, 1268, 1131, 1083, 1000, 749, 695, cm−1. 1H
NMR (400 MHz, CDCl3) δ = 7.71 (d, J = 7.8 Hz, 1H), 7.42−7.31
(m, 5H), 7.31−7.20 (m, 11H), 7.00 (d, J = 7.5 Hz, 1H), 2.84−2.71
(m, 2H), 2.33 (s, 3H), 1.59−1.52 (m, 2H), 1.40 (dt, J = 14.2, 7.1 Hz,
2H), 1.33−1.26 (m, 4H), 0.87 (t, J = 7.0 Hz, 3H) ppm. 13C NMR
(100 MHz, CDCl3) δ = 149.1, 146.0, 144.0, 141.0, 136.8, 133.9,
129.7, 128.2, 128.0, 127.7, 127.5, 127.4, 127.2, 126.5, 125.8, 124.3,
123.4, 114.3, 92.0, 31.7, 31.5, 29.4, 29.1, 22.6, 21.6, 14.1 ppm. HRMS
(ESI) m/z: [M + H]+ Calcd for C34H35O 459.2682; Found 459.2719.
(Z)-3-(Cyclopropyl(naphthalen-1-yl)methylene)-1,1-dimethyl-
1,3-dihydroisobenzofuran (4gd). GP-2 was carried out with 2-(2-
(cyclopropylethynyl)phenyl)propan-2-ol 1g (40 mg, 0.2 mmol), 1-
bromonaphathalene 2d (50 mg, 0.24 mmol), Pd(OAc)2 (2 mg, 0.01
mmol), PPh3 (8 mg, 0.03 mmol), Cs2CO3 (130 mg, 0.4 mmol), and
toluene (2 mL) at 80 °C, for 6 h. Purification of the crude material by
silica gel column chromatography (petroleum ether/ethyl acetate,
100:0 to 95:05) furnished the product 4gd (54 mg, 83%) as a pale
yellow liquid.
Hz, 1H), 7.74 (d, J = 7.1 Hz, 1H), 7.60 (td, J = 7.6, 1.5 Hz, 1H),
7.41−7.33 (m, 4H), 7.22−7.17 (m, 1H), 2.71 (dd, J = 13.8, 6.9 Hz,
2H), 1.64−1.49 (m, 4H), 1.41 (s, 6H), 1.29−1.25 (m, 4H), 0.86 (d, J
= 6.8 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 193.5,
150.4, 150.1, 145.8, 133.9, 133.6, 131.7, 129.3, 128.7, 128.0, 126.5,
126.4, 123.4, 120.8, 107.5, 85.9, 32.5, 31.6, 29.4, 29.2, 28.9, 22.6, 14.0
ppm. HRMS (ESI) m/z: [M + H]+ Calcd for C24H29O2 349.2162;
Found 349.2144.
(Z)-6-Chloro-1,1-dimethyl-3-(1-phenylheptylidene)-1,3-dihydroi-
sobenzofuran (4ka). GP-2 was carried out with 2-(5-chloro-2-(oct-1-
yn-1-yl)phenyl)propan-2-ol 1k (52 mg, 0.2 mmol), bromobenzene 2a
(38 mg, 0.24 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8 mg, 0.03
mmol), Cs2CO3 (130 mg, 0.4 mmol), and toluene (2 mL) at 80 °C,
for 6 h. Purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate, 100:0 to 95:05)
furnished the product 4ka (52 mg, 73%) as a colorless oil.
[TLC (petroleum ether/ethyl acetate 90:10, Rf (1k) = 0.6, Rf (4ka)
= 0.5, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax = 2892,
2797, 2705, 1673, 1587, 1288, 1197, 1155, 836, 798, 747, 722 cm−1
.
1H NMR (400 MHz, CDCl3) δ 7.54 (dd, J = 8.3, 1.4 Hz, 3H), 7.36−
7.29 (m, 3H), 7.21−7.16 (m, 1H), 7.15 (d, J = 1.9 Hz, 1H), 2.76−
2.64 (m, 2H), 1.54−1.47 (m, 8H), 1.36 (dd, J = 14.1, 7.5 Hz, 2H),
1.30−1.25 (m, 4H), 0.86 (t, J = 6.7 Hz, 3H) ppm. 13C NMR (100
MHz, CDCl3) δ = 151.5, 148.6, 141.1, 133.6, 131.9, 128.7, 128.1,
127.7, 125.8, 124.4, 121.1, 113.2, 85.0, 31.7, 31.4, 29.4, 29.0, 28.2,
22.6, 14.1 ppm. HRMS (ESI) m/z: [M + H]+ Calcd for C23H28ClO
355.1823; Found 355.1794.
(Z)-1-Methyl-1-propyl-3-(1-(p-tolyl)hexylidene)-1,3-dihydroiso-
benzofuran (4ec). GP-2 was carried out with 2-(2-(hept-1-yn-1-
yl)phenyl)pentan-2-ol 1e (52 mg, 0.2 mmol), 4-bromotoluene 2c (41
mg, 0.24 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8 mg, 0.03
mmol), Cs2CO3 (195 mg, 0.4 mmol), and toluene (2 mL) at 80 °C,
for 6 h. Purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate, 100:0 to 95:05)
furnished the product 4ec (48 mg, 69%) as a colorless oil.
[TLC (petroleum ether/ethyl acetate 95:05, Rf (1g) = 0.3, Rf (4gd)
= 0.5, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax = 2895,
2830, 1656, 1581, 1440, 1362, 1251, 1163, 1102, 994, 960, 797, 726
cm−1. 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 7.7 Hz, 1H), 8.00−
7.93 (m, 1H), 7.89−7.84 (m, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.51−
7.39 (m, 4H), 7.33 (dd, J = 7.0, 1.2 Hz, 1H), 7.25−7.16 (m, 2H), 2.24
(tt, J = 8.3, 5.2 Hz, 1H), 1.40 (d, J = 18.1 Hz, 6H), 0.89−0.82 (m,
1H), 0.81−0.71 (m, 1H), 0.32 (td, J = 9.6, 5.4 Hz, 1H), 0.20 (td, J =
9.6, 5.3 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 152.3,
150.1, 137.8, 133.6, 133.0, 132.2, 128.1, 128.0, 127.6, 127.1, 126.8,
126.5, 125.3, 125.2, 125.0, 124.1, 120.5, 110.0, 85.7, 28.6, 28.0, 13.4,
[TLC (petroleum ether/ethyl acetate 95:05, Rf (1e) = 0.3, Rf (4ec)
= 0.5, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax = 2926,
2896, 2838, 1746, 1496, 1443, 1267, 1209, 1126, 1090, 913, 802, 750,
1
692 cm−1. H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.6 Hz, 1H),
8194
https://doi.org/10.1021/acs.joc.1c00666
J. Org. Chem. 2021, 86, 8182−8196

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
7.6, 7.6 ppm. HRMS (ESI) m/z: [M + H]+ Calcd for C24H23O
327.1743; Found 327.1730.
0.03 mmol), Cs2CO3 (130 mg, 0.4 mmol), and toluene (2 mL) at 80
°C, for 6 h. Purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate, 100:0 to 95:05)
furnished the product 4im:3im (16:5, 47 mg, 49%) as a colorless oil.
[TLC (petroleum ether/ethyl acetate 90:10, Rf (1i) = 0.5, Rf (4im)
= 0.4, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax = 2924,
(Z)-3-(Cyclopropyl(3-fluoro-4-nitrophenyl)methylene)-1,1-di-
methyl-1,3-dihydroisobenzofuran (4gk). GP-2 was carried out with
2-(2-(cyclopropylethynyl)phenyl)propan-2-ol 1g (40 mg, 0.2 mmol),
4-bromo-2-fluoro-1-nitrobenzene 2k (53 mg, 0.24 mmol), Pd(OAc)2
(2 mg, 0.01 mmol), PPh3 (8 mg, 0.03 mmol), Cs2CO3 (130 mg, 0.4
mmol), and toluene (2 mL) at 80 °C, for 6 h. Purification of the crude
material by silica gel column chromatography (petroleum ether/ethyl
acetate, 100:0 to 95:05) furnished the product 4gk (40 mg, 59%) as a
pale yellow liquid.
1
2895, 2827, 1750, 1703, 1446, 1264, 1088, 899, 751, 721 cm−1. H
NMR (400 MHz, CDCl3) δ 8.04−7.97 (m, 2H), 7.70 (d, J = 7.4 Hz,
1H), 7.69−7.63 (m, 2H), 7.37 (ddt, J = 8.3, 7.3, 3.8 Hz, 2H), 7.27 (d,
J = 4.4 Hz, 1H), 5.42 (dd, J = 7.7, 3.8 Hz, 1H), 3.92 (s, 3H), 2.89−
2.68 (m, 2H), 1.88 (dddd, J = 14.0, 9.9, 6.0, 3.9 Hz, 1H), 1.76−1.64
(m, 1H), 1.54−1.24 (m, 8H), 0.95 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.1
Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 167.3, 152.2,
146.4, 145.2, 133.8, 129.1, 128.5, 128.3, 128.1, 126.9, 123.6, 121.3,
111.4, 83.3, 51.9, 38.2, 31.9, 30.7, 28.9, 22.6, 18.4, 14.1, 14.1 ppm.
HRMS (ESI) m/z: [M + H]+ Calcd for C25H31O3 379.2268; Found
379.2259.
[TLC (petroleum ether/ethyl acetate 90:10, Rf (1g) = 0.5, Rf (4gk)
= 0.4, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax = 2892,
2826, 1644, 1576, 1510, 1452, 1328, 1250, 1172, 1085, 1047, 881,
1
708 cm−1. H NMR (400 MHz, CDCl3) δ 8.26−8.18 (m, 1H), 8.03
(t, J = 8.5 Hz, 1H), 7.74−7.60 (m, 2H), 7.47−7.40 (m, 2H), 7.29−
7.26 (m, 1H), 1.93 (tt, J = 8.0, 5.2 Hz, 1H), 1.60 (s, 6H, 2 × CH3),
1.23−1.06 (m, 2H), 0.50−0.33 (m, 2H) ppm. 13C{1H} NMR (100
MHz, CDCl3) δ 157.5, 155.3 (d, Jc‑f = 259 Hz), 150.1, 132.2, 129.6,
128.9, 127.9, 125.8, 124.9 (d, Jc‑f = 2 Hz), 124.7 (d, Jc‑f = 3 Hz), 120.4,
117.8 (d, Jc‑f = 21 Hz), 109.1, 88.0, 28.3, 11.5, 11.4 ppm. HRMS
(ESI) m/z: [M + H]+ Calcd for C20H19FNO3 340.1343; Found
340.1328.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00666.
■
sı
(Z)-1,1-Dimethyl-3-(1-(naphthalen-1-yl)nonylidene)-1,3-dihy-
droisobenzofuran (4cd). GP-2 was carried out with 2-(2-(dec-1-yn-
1-yl)phenyl)propan-2-ol 1c (54 mg, 0.2 mmol), 1-bromonaphatha-
lene 2d (50 mg, 0.24 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8
mg, 0.03 mmol), Cs2CO3 (130 mg, 0.4 mmol), and toluene (2 mL) at
80 °C, for 6 h. Purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate, 100:0 to 98:2)
furnished the product 4cd (70 mg, 88%) as a colorless oil.
Spectral data for all new compounds and crystallo-
graphic data (PDF)
Accession Codes
CCDC 2071793 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
[TLC (petroleum ether/ethyl acetate 95:05, Rf (1c) = 0.3, Rf (4cd)
= 0.5, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νma1x = 2893,
2823, 1643, 1447, 1255, 1132, 1080, 897,770, 721 cm−1. H NMR
(400 MHz, CDCl3) δ 7.96 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.0 Hz,
1H), 7.79 (dd, J = 10.6, 8.2 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.40 (tt,
J = 21.0, 7.0 Hz, 5H), 7.20 (d, J = 7.4 Hz, 1H), 2.81 (t, J = 8.1 Hz,
2H), 1.58−1.48 (m, 2H), 1.37 (d, J = 11.5 Hz, 6H), 1.33−1.15 (m,
10H), 0.86 (t, J = 6.7 Hz, 3H) ppm. 13C{1H} NMR (100 MHz,
CDCl3) δ 150.1, 149.4, 140.6, 133.7, 132.8, 131.7, 128.1, 128.0, 127.8,
126.8, 126.5, 126.2, 125.5, 125.3, 125.0, 123.2, 120.7, 110.7, 85.1,
33.3, 31.8, 29.8, 29.5, 29.3, 28.8, 28.8, 28.0, 22.6, 14.1 ppm. HRMS
(ESI) m/z: [M + H]+ Calcd for C29H35O 399.2682; Found 399.2877.
(Z)-4-(((6-(Cyclopropyl(3,3-dimethylisobenzofuran-1(3H)-
ylidene)methyl)naphthalen-2-yl)oxy)methyl)benzonitrile (4gh).
GP-2 was carried out with 2-(2-(cyclopropylethynyl)phenyl)propan-
2-ol 1g (40 mg, 0.2 mmol), 4-(((6-bromonaphthalen-2-yl)oxy)-
methyl)benzonitrile 2h (81 mg, 0.24 mmol), Pd(OAc)2 (2 mg, 0.01
mmol), PPh3 (8 mg, 0.03 mmol), Cs2CO3 (130 mg, 0.4 mmol), and
toluene (2 mL) at 80 °C, for 6 h. Purification of the crude material by
silica gel column chromatography (petroleum ether/ethyl acetate,
100:0 to 95:05) furnished the product 4gh:3gh (16:5, 69 mg, 76%) as
a pale yellow liquid.
AUTHOR INFORMATION
Corresponding Author
■
Gedu Satyanarayana − Department of Chemistry, Indian
Institute of Technology, 502 285 Sangareddy, Telangana,
India; orcid.org/0000-0002-6410-5421; Phone: (040)
2301 6251; Email: gvsatya@chy.iith.ac.in; Fax: (040)
2301 6003/32
Author
Chinnabattigalla Sreenivasulu − Department of Chemistry,
Indian Institute of Technology, 502 285 Sangareddy,
Telangana, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00666
Notes
[TLC (petroleum ether/ethyl acetate 90:10, Rf (1g) = 0.5, Rf (4gh)
= 0.6, UV detection]. IR (MIR-ATR, 4000−600 cm−1): νmax = 3028,
2893, 2827, 2206, 1715, 1609, 1579, 1484, 1447, 1372, 1247, 1192,
1155, 1082, 1047, 944, 897, 844, 807, 747 cm−1. 1H NMR (400 MHz,
CDCl3) δ 8.22−8.14 (m, 1H), 7.99 (d, J = 1.0 Hz, 1H), 7.78−7.72
(m, 2H), 7.70−7.62 (m, 3H), 7.58 (d, J = 8.4 Hz, 2H), 7.42−7.31 (m,
2H), 7.19 (ddd, J = 11.4, 7.8, 2.1 Hz, 2H), 7.12 (d, J = 2.5 Hz, 1H),
5.22 (s, 2H), 2.05 (tt, J = 8.1, 5.2 Hz, 1H), 1.55 (s, 6H), 1.08−1.00
(m, 2H), 0.45−0.37 (m, 2H) ppm. 13C{1H} NMR (100 MHz,
CDCl3) δ 155.6, 153.2, 149.6, 142.6, 136.5, 133.2, 132.4, 132.3, 129.8,
129.2, 129.0, 128.2, 127.6, 127.5, 125.3, 124.8, 120.3, 118.7, 118.1,
111.6, 111.6, 107.1, 86.1, 68.8, 28.4, 12.5, 10.3 ppm. HRMS (ESI) m/
z: [M + H]+ Calcd for C32H28NO2 458.2115; Found 458.2099.
(Z)-1-(4-(1-(3-Propylisobenzofuran-1(3H)-ylidene)hexyl)phenyl)-
ethan-1-one (4im). GP-2 was carried out with 1-(2-(hept-1-yn-1-
yl)phenyl)butan-1-ol 1i (49 mg, 0.2 mmol), methyl 4-bromobenzoate
2m (52 mg, 0.24 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (8 mg,
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the Department of Science and Technology-
Science and Engineering Research Board (DST-SERB) [No.
EMR/2017/005312], New Delhi, for the financial support.
C.S. thanks UGC for the award of the research fellowship.
REFERENCES
■
(1) Sekine, K.; Takayanagi, A.; Kikuchi, S.; Yamada, T. Silver-
Catalyzed C-C Bond Formation with Carbon Dioxide: Significant
Synthesis of Dihydroisobenzofurans. Chem. Commun. 2013, 49 (96),
11320−11322.
(2) Kwon, Y.-J.; Sohn, M.-J.; Kim, C.-J.; Koshino, H.; Kim, W.-G.
Flavimycins A and B, Dimeric 1,3-Dihydroisobenzofurans with
8195
https://doi.org/10.1021/acs.joc.1c00666
J. Org. Chem. 2021, 86, 8182−8196

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Peptide Deformylase Inhibitory Activity from Aspergillus Flavipes. J.
Nat. Prod. 2012, 75 (2), 271−274.
(3) Abdelfattah, M. S.; Arai, M. A.; Ishibashi, M. Bioactive
Secondary Metabolites with Unique Aromatic and Heterocyclic
Structures Obtained from Terrestrial Actinomycetes Species. Chem.
Pharm. Bull. 2016, 64 (7), 668−675.
(4) Harper, J. K.; Arif, A. M.; Ford, E. J.; Strobel, G. A.; Porco, J. A.;
Tomer, D. P.; Oneill, K. L.; Heider, E. M.; Grant, D. M. Pestacin: A
1,3-Dihydro Isobenzofuran from Pestalotiopsis Microspora Possessing
Antioxidant and Antimycotic Activities. Tetrahedron 2003, 59 (14),
2471−2476.
(5) Yang, J.; Huang, R.; Qiu, S. X.; She, Z.; Lin, Y. A New
Isobenzofuranone from the Mangrove Endophytic Fungus Penicillium
Sp. (ZH58). Nat. Prod. Res. 2013, 27 (20), 1902−1905.
(6) Mousavi, S. H.; Mohammadizadeh, M. R.; Roshan, Z.;
Jamaleddini, A.; Arimitsu, S. One-Pot Synthesis of Spiro-Isobenzofur-
an Compounds via the Sequential Condensation/Oxidation Reaction
of Ninhydrin with 4-Amino-1,2-Naphthoquinones/2-Amino-1,4-
Naphthoquinones under Mild Conditions. ACS Omega 2020, 5
(29), 18273−18288.
(7) Coote, S. J.; Davies, S. G.; Middlemiss, D.; Naylor, A.
Stereoselective Synthesis of Cis-1,3-Disubstituted 1,3-Dihydroisoben-
zofurans via Arenechromium Tricarbonyl Methodology. J. Organomet.
Chem. 1989, 379 (1), 81−88.
(8) Gözler, B.; Gözler, T.; Shamma, M. Egenine: A Possible
Intermediate in Phthalideisoquinoline Biogenesis. Tetrahedron 1983,
39 (4), 577−580.
(9) Jing, L.; Wenzao, L.; Guoshi, T. Two Phthalideisoquinoline
Hemiacetal Alkaloids from Corydalis Decumbens. Planta Med. 1994,
60 (5), 486−487.
(10) Sekine, K.; Takayanagi, A.; Kikuchi, S.; Yamada, T. Silver-
Catalyzed C-C Bond Formation with Carbon Dioxide: Significant
Synthesis of Dihydroisobenzofurans. Chem. Commun. 2013, 49 (96),
11320−11322.
(11) Praveen, C.; Iyyappan, C.; Girija, K.; Kumar, K. S.; Perumal, P.
T. Regioselective Synthesis and Evaluation of 3-Alkylidene-1,3-
Dihydroisobenzofurans as Potential Antidepressant Agents. J. Chem.
Sci. 2012, 124 (2), 451−462.
(12) Liu, S.; Chen, K.; Hao, W.-J.; Tu, X.-C.; Tu, S.-J.; Jiang, B.
Generation of 1,3-Dimethylene-Substituted Isobenzofurans via Pd-
(II)-Catalyzed Selective Oxo-Cyclization/SO2 Insertion Cascade of
β-Alkynyl Ketones. J. Org. Chem. 2019, 84 (4), 1964−1971.
(13) Peuchmaur, M.; Lisowski, V.; Gandreuil, C.; Maillard, L. T.;
Martinez, J.; Hernandez, J.-F. Solid-Phase Synthesis of Isocoumarins:
A Traceless Halocyclization Approach. J. Org. Chem. 2009, 74 (11),
4158−4165.
(14) Yao, T.; Larock, R. C. Regio- and Stereoselective Synthesis of
Isoindolin-1-Ones via Electrophilic Cyclization. J. Org. Chem. 2005,
70 (4), 1432−1437.
(15) Mehta, S.; Yao, T.; Larock, R. C. Regio- and Stereoselective
Synthesis of Cyclic Imidates via Electrophilic Cyclization of 2-(1-
Alkynyl)benzamides. A Correction. J. Org. Chem. 2012, 77 (23),
10938−10944.
(16) Wei, L.-L.; Wei, L.-M.; Lin, P.-Y.; Chen, C.-C.; Pan, W.-B.; Wu,
M.-J. Palladium(0)-Catalyzed 5-Exo-Dig O-Cyclization/Coupling of
Ethyl 3-(2-Alkynylphenyl)-3-Oxopropanoates with Aryl Iodides to
1,3-Dihydroisobenzofurans. Tetrahedron Lett. 2015, 56 (47), 6629−
6632.
(17) Bacchi, A.; Costa, M.; Della Ca, N.; Fabbricatore, M.; Fazio, A.;
Gabriele, B.; Nasi, C.; Salerno, G. Synthesis of 1-(Alkoxycarbonyl)-
Methylene-1,3-Dihydroisobenzofurans and 4-(Alkoxycarbonyl)Benzo-
[c]Pyrans by Palladium-Catalysed Oxidative Carbonylation of 2-
Alkynylbenzyl Alcohols, 2-Alkynylbenzaldehydes and 2-Alkynylphenyl
Ketones. Eur. J. Org. Chem. 2004, 2004 (3), 574−585.
(18) Gabriele, B.; Salerno, G.; Fazio, A.; Pittelli, R. Versatile
Synthesis of (Z)-1-Alkylidene-1,3-Dihydroisobenzofurans and 1H-
Isochromenes by Palladium-Catalyzed Cycloisomerization of 2-
Alkynylbenzyl Alcohols. Tetrahedron 2003, 59 (33), 6251−6259.
(19) Zhao, X.; Miao, Z.; Chen, R. Efficient Syntheses of 1H-
Isochromen-1-Ylmethylphosphonates via Regioselective 6-Endo-Dig
Addition to CarbonCarbon Triple Bond Catalyzed by Pd(OAc)2.
Phosphorus, Sulfur Silicon Relat. Elem. 2011, 186 (12), 2357−2367.
(20) Sun, J.; Qiu, J.-K.; Wu, Y.-N.; Hao, W.-J.; Guo, C.; Li, G.; Tu,
S.-J.; Jiang, B. Silver-Mediated Radical C(Sp3)-H Biphosphinylation
and Nitration of β-Alkynyl Ketones for Accessing Functional
Isochromenes. Org. Lett. 2017, 19 (4), 754−757.
(21) Wang, D.; Liu, S.; Lan, X.-C.; Paniagua, A.; Hao, W.-J.; Li, G.;
Tu, S.-J.; Jiang, B. Tunable Dimerization and Trimerization of β-
Alkynyl Ketones via Silver Catalysis for Accessing Spiro and Dispiro
Compounds Containing 1H-Isochromene. Adv. Synth. Catal. 2017,
359 (18), 3186−3193.
(22) Liu, S.; Chen, K.; Lan, X.-C.; Hao, W.-J.; Li, G.; Tu, S.-J.; Jiang,
B. Synergistic Silver/Scandium Catalysis for Divergent Synthesis of
Skeletally Diverse Chromene Derivatives. Chem. Commun. 2017, 53
(77), 10692−10695.
(23) Liu, S.; Lan, X.-C.; Chen, K.; Hao, W.-J.; Li, G.; Tu, S.-J.; Jiang,
B. Ag/Brønsted Acid Co-Catalyzed Spiroketalization of β-Alkynyl
Ketones toward Spiro[Chromane-2,1′-Isochromene] Derivatives. Org.
Lett. 2017, 19 (14), 3831−3834.
(24) Shi, H.-N.; Huang, M.-H.; He, C.-L.; Lu, H.-P.; Hao, W.-J.; Tu,
X.-C.; Tu, S.-J.; Jiang, B. Completely Stereoselective Synthesis of
Sulfonated 1,3-Dihydroisobenzofurans via Radical Multicomponent
Reactions. J. Org. Chem. 2019, 84 (21), 13686−13695.
(25) Mancuso, R.; Mehta, S.; Gabriele, B.; Salerno, G.; Jenks, W. S.;
Larock, R. C. A Simple and Mild Synthesis of 1H-Isochromenes and
(Z)-1-Alkylidene-1,3-Dihydroisobenzofurans by the Iodocyclization
of 2-(1-Alkynyl)Benzylic Alcohols. J. Org. Chem. 2010, 75 (3), 897−
901.
(26) Della Ca, N.; Campanini, F.; Gabriele, B.; Salerno, G.; Massera,
C.; Costa, M. Cascade Reactions: Catalytic Synthesis of Function-
alized 1,3-Dihydroisobenzofuran and Tetrahydrofuran Derivatives by
Sequential Nucleophilic Ring Opening-Heterocyclization- Oxidative
Carbonylation of Alkynyloxiranes. Adv. Synth. Catal. 2009, 351 (14−
15), 2423−2432.
(27) Cao, Z.; Li, S.; Li, J.; Meng, X.; Zhang, H.; Sun, X.; You, J.
Gold-Catalyzed π-Directed Regioselective Cyclization of Bis(o-
Alkynyl Benzyl Alcohols): Rapid Access to Dihydroisobenzofuran
Derivatives. New J. Chem. 2016, 40 (10), 8211−8215.
(28) Yu, S.-Y.; Gao, L.-H.; Wu, J.-X.; Lan, H.-B.; Ma, Y.; Yin, Z.-G.
Regio- and Stereoselective Intramolecular Hydroalkoxylation of
Aromatic Alkynols: An Access to Dihydroisobenzofurans under
Transition-Metal-Free Conditions. Chem. Pap. 2020, 74 (10),
3303−3310.
(29) Mahendar, L.; Gopi Krishna Reddy, A.; Krishna, J.;
Satyanarayana, G. [Cu]-Catalyzed Domino Sonogashira Coupling
Followed by Intramolecular 5-Exo-Dig Cyclization: Synthesis of 1,3-
Dihydro-2-Benzofurans. J. Org. Chem. 2014, 79 (18), 8566−8576.
(30) Nandakumar, A.; Kiruthika, S. E.; Naveen, K.; Perumal, P. T.
Pd(0)-Catalyzed Regio- and Stereoselective Cyclization of Alkynes:
Selective Synthesis of (E)-4-(Isobenzofuran-1(3H)-Ylidene)-1,2,3,4-
Tetrahydroisoquinolines and Aze/Oxepinoindoles. Org. Biomol.
Chem. 2014, 12 (6), 876−880.
(31) Peng, P.; Tang, B.-X.; Pi, S.-F.; Liang, Y.; Li, J.-H. Synthesis of
(E)-3-(Isobenzofuran-3(1H)-Ylidene)Indolin-2-Ones by the Palladi-
um-Catalyzed Intramolecular C-H Functionalization Process. J. Org.
Chem. 2009, 74 (9), 3569−3572.
́
(32) Madich, Y.; Alvarez, R.; Aurrecoechea, J. M. Palladium-
Catalyzed Regioselective 5-Exo-O-Cyclization/Oxidative Heck Cas-
cades from o-Alkynylbenzamides and Electron-Deficient Alkenes. Eur.
J. Org. Chem. 2014, 2014 (28), 6263−6271.
́
(33) Kołodziejczyk, A.; Domanski, S.; Chaładaj, W. Tandem
Palladium-Catalyzed 6-Exo-Dig Oxocyclization Coupling of δ-
Acetylenic β-Ketoesters with Aryl Bromides and Chlorides: Route
to Substituted Dihydropyrans. J. Org. Chem. 2018, 83 (20), 12887−
12896.
8196
https://doi.org/10.1021/acs.joc.1c00666
J. Org. Chem. 2021, 86, 8182−8196